N-(pyrid-4-yl)amides and n-(pyrimidin-4-yl)amides and their pharmaceutical and cosmetic use

ABSTRACT

The present invention relates generally to the field of pharmaceuticals and cosmetics. More specifically, the present invention pertains to certain N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides of the following formula which are potent modulators (e.g., inhibitors) of an androgen receptor, and which are useful, for example, in therapy, for example, in the treatment of a dermatological disease or disorder; a disease or disorder of the sebaceous gland(s); acne; hyperseborrhoea; oily skin; seborrhoeic dermatitis; hyperpilosity or hirsutism; atopic dermatitis; or androgenic alopecia; especially acne. The present invention also relates to compositions (e.g., pharmaceutical compositions, cosmetic compositions) comprising the compounds; methods of preparing the compositions; methods of modulating (e.g., inhibiting) an androgen receptor using the compounds and/or compositions; and medical and/or cosmetic use of the compounds and compositions.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/355,810, filed on May 1, 2014, now U.S. patent Ser. No. ______, whichis the National Stage Entry of PCT/EP2012/071811, filed on Nov. 5, 2012,and designating the United States (published in English on May 10, 2013,as WO 2013/064681 A1), which claims priority under 35 U.S.C. §119 toU.S. Provisional Application No. 61/555,583, filed Nov. 4, 2011, andFrench Patent Application No. 1159997, filed Nov. 4, 2011. The contentsof each hare hereby expressly incorporated by reference in its entiretyand each assigned to the assignee thereof.

TECHNICAL FIELD

The present invention relates generally to the field of pharmaceuticalsand cosmetics. More specifically, the present invention pertains tocertain N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides, as describedherein, which are potent modulators (e.g., inhibitors) of an androgenreceptor, and which are useful, for example, in therapy, for example, inthe treatment of a dermatological disease or disorder; a disease ordisorder of the sebaceous gland(s); acne; hyperseborrhoea; oily skin;seborrhoeic dermatitis; hyperpilosity or hirsutism; atopic dermatitis;or androgenic alopecia; especially acne. The present invention alsorelates to compositions (e.g., pharmaceutical compositions, cosmeticcompositions) comprising the compounds; methods of preparing thecompositions; methods of modulating (e.g., inhibiting) an androgenreceptor using the compounds and/or compositions; and medical and/orcosmetic use of the compounds and compositions.

BACKGROUND

A number of patents and publications are cited herein in order todescribe and disclose the invention more fully and the state of the artto which the invention pertains. Each of these references isincorporated herein by reference in its entirety into the presentdisclosure, to the same extent as if each individual reference wasspecifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims that follow, unlessthe context requires otherwise, the word “comprise,” and variations suchas “comprises” and “comprising,” will be understood to imply theinclusion of a stated integer or step or group of integers or steps butnot the exclusion of any other integer or step or group of integers orsteps.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a pharmaceutical carrier” includes mixtures of two or moresuch carriers, and the like.

Ranges are often expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by the use of the antecedent “about,” itwill be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understandingthe present invention. It is not an admission that any of theinformation provided herein is prior art or relevant to the presentlyclaimed invention, or that any publication specifically or implicitlyreferenced is prior art.

The present invention relates to the provision of new amides that arepotent modulators of androgen receptors.

Documents describing known modulators of androgen receptors include EP 0079 191; WO 2010/143803; CN 1597662; WO 2004/064747; and WO 2005/000794.

SUMMARY OF THE INVENTION

One aspect of the present invention pertains to certainN-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides, and pharmaceuticallyacceptable salts, hydrates, and solvates thereof, as described herein.

Another aspect of the present invention pertains to a composition (e.g.,a pharmaceutical composition; a physiologically acceptable composition;a cosmetic composition) comprising an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein, and a carrier, diluent, orexcipient (e.g., a pharmaceutically acceptable carrier, diluent, orexcipient; a physiologically acceptable carrier, diluent, or excipient;a cosmetic carrier, diluent, or excipient).

Another aspect of the present invention pertains to a method ofpreparing a composition (e.g., a pharmaceutical composition; aphysiologically acceptable composition; a cosmetic composition)comprising mixing an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, asdescribed herein, and a carrier, diluent, or excipient (e.g., apharmaceutically acceptable carrier, diluent, or excipient; aphysiologically acceptable carrier, diluent, or excipient; a cosmeticcarrier, diluent, or excipient).

Another aspect of the present invention pertains to a method ofmodulating (e.g., inhibiting) an androgen receptor, in vitro or in vivo,comprising contacting the androgen receptor with an effective amount ofan N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein.

Another aspect of the present invention pertains to a method ofmodulating (e.g., inhibiting) an androgen receptor in a cell, in vitroor in vivo, comprising contacting the cell with an effective amount ofan N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein.

Another aspect of the invention is an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide as described herein for use in a method oftreatment of the human or animal body.

Another aspect of the invention is an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide as described herein for use in a method oftreatment of a disease or disorder.

Another aspect of the invention is use of an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide as described herein in the manufacture of amedicament for the treatment of a disease or disorder.

Another aspect of the invention is a method of treatment of a disease ordisorder comprising administering a therapeutically-effective amount ofan N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide as described herein toa patient in need of said treatment.

In one embodiment, the treatment is treatment of a disease or disorderthat is ameliorated by the modulation (e.g., inhibition) of an androgenreceptor.

In one embodiment, the treatment is treatment of an androgen-dependentdisease or disorder.

In one embodiment, the treatment is treatment of a dermatologicaldisease or disorder; a disease or disorder of the sebaceous gland(s);acne; hyperseborrhoea; oily skin; seborrhoeic dermatitis; hyperpilosityor hirsutism; atopic dermatitis; or androgenic alopecia.

In one embodiment, the treatment is treatment of acne.

Another aspect of the invention pertains to a kit comprising (a) anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide as described herein, or acomposition (e.g., a pharmaceutical composition; a physiologicallyacceptable composition; a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide as described herein,e.g., preferably provided in a suitable container and/or with suitablepackaging; and (b) instructions for use, e.g., written instructions onhow to administer the compound or composition.

Another aspect of the present invention pertains to a physiologicallyacceptable composition (e.g., a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a non-therapeutic method (e.g., a cosmetic method) of body careand/or hair care.

Another aspect of the present invention pertains to a non-therapeuticmethod (e.g., a cosmetic method) of body care and/or hair care,comprising applying to the body and/or hair of a subject an effectiveamount of an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, asdescribed herein, preferably in the form of a physiologically acceptablecomposition (e.g., a cosmetic composition).

Another aspect of the present invention pertains to use of anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, ina non-therapeutic method (e.g., a cosmetic method) of body care and/orhair care.

Another aspect of the present invention pertains to anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a non-therapeutic method (e.g., a cosmetic method) of body careand/or hair care.

Another aspect of the present invention pertains to use of anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, inthe manufacture of physiologically acceptable composition (e.g., acosmetic composition) for use in a non-therapeutic method of body careand/or hair care.

Another aspect of the present invention pertains to a non-therapeuticmethod (e.g., a cosmetic method) of body care and/or hair care,comprising applying to the body and/or hair of a subject an effectiveamount of a physiologically acceptable composition (e.g., a cosmeticcomposition) comprising an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein.

Another aspect of the present invention pertains to use of aphysiologically acceptable composition (e.g., a cosmetic composition)comprising an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, asdescribed herein in a non-therapeutic method (e.g., a cosmetic method)of body care and/or hair care.

Another aspect of the present invention pertains to a physiologicallyacceptable composition (e.g., a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a non-therapeutic method (e.g., a cosmetic method) of body careand/or hair care.

Another aspect of the present invention is an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide as described herein obtainable by a method ofsynthesis as described herein, or a method comprising a method ofsynthesis as described herein.

Another aspect of the present invention is an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide as described herein obtained by a method ofsynthesis as described herein, or a method comprising a method ofsynthesis as described herein.

Another aspect of the present invention is a novel intermediate, asdescribed herein, which is suitable for use in the methods of synthesisdescribed herein.

Another aspect of the present invention is the use of such novelintermediates, as described herein, in the methods of synthesisdescribed herein.

As will be appreciated by one of skill in the art, features andpreferred embodiments of one aspect of the invention will also pertainto other aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

The present invention relates to certain N-(pyrid-4-yl)amides andN-(pyrimidin-4-yl)amides which are structurally related to2-hydroxy-N-(pyrid-4-yl)-acetamide and2-hydroxy-N-(pyrimidin-4-yl)-acetamide.

Thus, one aspect of the present invention pertains to compounds offormula (1), and pharmaceutically acceptable salts, hydrates, andsolvates thereof, wherein X, —R¹, —R², —R³, and —R⁴ are as definedherein:

In one embodiment:

-   -   R¹ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(m)—C₁₋₆        alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆ alkyl-OH,        —(CH₂)_(i)—C₁₋₆ alkyloxy, —(CH₂)_(j)—O—C₁₋₆ fluoroalkyl,        COR^(a), CN, NO₂, NR⁵R⁶, or a halogen atom;    -   R² is a hydrogen atom, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆        alkyloxy, —S(O)_(n)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆        fluoroalkyloxy, C₁₋₆ alkyl-OH, —(CH₂)_(k)—C₁₋₆ alkyloxy,        —(CH₂)_(l)—O—C₁₋₆ fluoroalkyl, COR^(b), CN, NO₂, NR^(5′)R^(6′),        OH, or a halogen atom;    -   R³ and R⁴ are identical or different and are a hydrogen atom,        C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, C₁₋₆ fluoroalkyl, —C₁₋₆ alkyl-OH,        —(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₉ cycloalkyl,        —(CH₂)_(r)—C₁₋₆ fluoroalkyl, —(CH₂)_(s)—O—C₁₋₆ fluoroalkyl,        phenyl, heteroaryl, heterocyclyl group, —(CH₂)_(t)-phenyl, or        —(CH₂)_(v)-heteroaryl, wherein each phenyl and heteroaryl is        optionally substituted with one to three identical or different        R^(c) groups;    -   and additionally, R³ and R⁴, together with the carbon atom        carrying them, may form a C₃₋₉ cycloalkyl group or a        heterocyclyl group, such as tetrahydrofuranyl,        tetrahydropyranyl, tetrahydrothiopyranyl,        tetrahydro-1-oxo-thiopyranyl, or        tetrahydro-1,1-dioxo-thiopyranyl;    -   R^(c) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,        —S(O)_(u)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy,        C₁₋₆ alkyl-OH, COR^(d), CN, NO₂, NR⁹R¹⁰, OH, or a halogen atom;    -   R^(a), R^(b), and R^(d) are identical or different and are C₁₋₆        alkyl, C₁₋₆ alkyloxy, or NR⁷R⁸;    -   R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹ and R¹⁰ are identical or        different and are a hydrogen atom, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        or —(CH₂)_(w)—C₃₋₇ cycloalkyl;    -   and additionally, R₅ and R₆, together with the nitrogen atom        carrying them, may form a heterocyclyl group, such as:        azetidinyl, pyrolidinyl, piperidinyl, azepanyl, morpholinyl, or        piperazinyl;    -   and additionally, R_(5′) and R_(6′), together with the nitrogen        atom carrying them, may form a heterocyclyl group, such as:        azetidinyl, pyrolidinyl, piperidinyl azepanyl, morpholinyl, or        piperazinyl;    -   and additionally, R₇ and R₈, together with the nitrogen atom        carrying them, may form a heterocyclyl group, such as:        azetidinyl, pyrolidinyl, piperidinyl, azepanyl, morpholinyl, or        piperazinyl;    -   and additionally, R₉ and R₁₀, together with the nitrogen atom        carrying them, may form a heterocyclyl group, such as:        azetidinyl, pyrolidinyl, piperidinyl, azepanyl, morpholinyl, or        piperazinyl;    -   i, j, k, l, p, q, r, s, t, v, and w are different or identical        and are 1, 2 or 3;    -   m, n, and u are different or identical and are 0, 1 or 2; and    -   X is CH or N.

Depending upon the values of R³ and R⁴, the carbon atom to which theyare attached may be chiral, and if so, may independently be in the (R)or (S) configuration. Unless otherwise indicated, it is intended thatboth configurations are encompassed. In one embodiment, theconfiguration is (S). In one embodiment, the configuration is (R).

The following is understood in the context of the invention:

-   -   C_(b-c), where b and c may assume values from 1 to 12, is a        carbon chain of b to c carbon atoms, for example C₁₋₆, being a        carbon chain that may have 1 to 6 carbon atoms.    -   alkyl is a linear or branched saturated aliphatic group, for        example a C₁₋₆ alkyl group is a linear or branched carbon chain        of 1 to 6 atom atoms, for example, methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,        isopentyl, hexyl, and isohexyl.    -   cycloalkyl is a cyclic, possibly branched, saturated carbon        chain comprising 3 to 7 carbon atoms, and a C₃₋₇ cycloalkyl        group is a carbon chain of 3 to 7 carbon atoms, for example,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and        cycloheptyl.    -   heterocyclyl is a cyclic or bicyclic, saturated or unsaturated        hydrocarbon chain comprising one or more heteroatoms selected        from O, S and N, including examples such as azetidinyl,        pyrolidinyl, piperidinyl azepanyl, morpholinyl, piperazinyl,        tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl.    -   heteroaryl is an aromatic heterocyclyl group, for example,        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,        oxadiazolyl, thiadiazolyl, triazolyl, and imidazolyl.    -   halogen is a fluorine, chlorine, or bromine atom.    -   alkyloxy is an —O-alkyl group.    -   fluoroalkyl is an alkyl group wherein one or more hydrogen atoms        has/have been replaced by a fluorine atom, for example, —CF₃.    -   fluoroalkyloxy is an alkyloxy group wherein one or more hydrogen        atoms has/have been replaced by a fluorine atom, for example,        —OCF₃.

In some preferred embodiments:

-   -   R¹ is a halogen atom, methyl, ethyl, isopropyl, trifluoromethyl,        nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl,        thioethyl, thio isopropyl, or methyl sulphone; and/or    -   R² is a hydrogen atom, a halogen atom, methyl, ethyl, isopropyl,        trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy,        thiomethyl, thioethyl, or thio isopropyl; and/or,    -   R³ and R⁴ are identical or different and are a hydrogen atom,        C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, —(CH₂)_(q)—C₃₋₉ cycloalkyl,        phenyl, heteroaryl, a heterocyclyl group,    -   —(CH₂)_(t)-phenyl, or —(CH₂)_(v)-heteroaryl, wherein each phenyl        and heteroaryl is optionally substituted with one to three        identical or different R^(c) groups.

In some more preferred embodiments:

-   -   R¹ is a halogen atom, methyl, ethyl, methoxy, ethoxy,        thiomethyl, thioethyl, trifluoromethyl, nitrile, or methyl        sulphone; and/or,    -   R² is a hydrogen atom, a chlorine atom, a bromine atom, methyl,        ethyl, methoxy, ethoxy, thiomethyl, thioethyl, or        trifluoromethyl; and/or,    -   R³ and R⁴ are identical or different and are a hydrogen atom,        C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, —(CH₂)_(q)—C₃₋₉ cycloalkyl,        phenyl, heteroaryl, a heterocyclyl group, —(CH₂)_(t)-phenyl, or        —(CH₂)_(v)-heteroaryl, wherein each phenyl and heteroaryl is        optionally substituted with one to three identical or different        R^(c) groups.

The Group X

In one embodiment, X is CH or N.

In one embodiment, X is CH.

In one embodiment, X is N.

The Group R¹

In one embodiment, R¹ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,—S(O)_(m)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆alkyl-OH, —(CH₂)_(i)—C₁₋₆ alkyloxy, —(CH₂)_(j)—O—C₁₋₆ fluoroalkyl,COR^(a), CN, NO₂, NR₅R₆, or a halogen atom.

In one embodiment, R¹ is a halogen atom, methyl, ethyl, isopropyl,trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy,thiomethyl, thioethyl, thio isopropyl, or methyl sulphone.

In one embodiment, R¹ is a halogen atom, methyl, ethyl, methoxy, ethoxy,thiomethyl, thioethyl, trifluoromethyl, nitrile, or methyl sulphone.

In one embodiment, R¹ is a halogen atom, methyl, ethyl, methoxy, ethoxy,trifluoromethyl, or nitrile.

In one embodiment, R¹ is a bromine atom or methoxy.

In one embodiment, R¹ is a bromine atom.

In one embodiment, R¹ is methoxy.

The Group R²

In one embodiment, R² is a hydrogen atom, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₁₋₆ alkyloxy, —S(O)_(n)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆fluoroalkyloxy, C₁₋₆ alkyl-OH, —(CH₂)_(k)—C₁₋₆ alkyloxy,—(CH₂)_(l)—O—C₁₋₆ fluoroalkyl, COR^(b), CN, NO₂, NR^(5′)R^(6′), OH, or ahalogen atom.

In one embodiment, R² is a hydrogen atom, a halogen atom, methyl, ethyl,isopropyl, trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy,thiomethyl, thioethyl, or thio isopropyl.

In one embodiment, R² is a hydrogen atom, a chlorine atom, a bromineatom, methyl, ethyl, methoxy, ethoxy, thiomethyl, thioethyl, ortrifluoromethyl.

In one embodiment, R² is a hydrogen atom, methyl, or methoxy.

In one embodiment, R² is a hydrogen atom or methoxy.

In one embodiment, R² is a hydrogen atom.

In one embodiment, R² is methoxy.

The Groups R³ and R⁴

In one embodiment, R³ and R⁴ are identical or different and are ahydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, C₁₋₆ fluoroalkyl, —C₁₋₆alkyl-OH, —(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₉ cycloalkyl,—(CH₂)_(r)—C₁₋₆ fluoroalkyl, —(CH₂)_(s)—O—C₁₋₆ fluoroalkyl, phenyl,heteroaryl, heterocyclyl, —(CH₂)_(t)-phenyl, or —(CH₂)_(v)-heteroaryl,wherein each phenyl and heteroaryl is optionally substituted with one tothree identical or different R^(c) groups; and additionally, R₃ and R₄,together with the carbon atom carrying them, may form a C₃₋₉ cycloalkylgroup or a heterocyclyl group, such as tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydro-1-oxo-thiopyranyl,or tetrahydro-1,1-dioxo-thiopyranyl.

In one embodiment, R³ and R⁴ are identical or different and are ahydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, C₁₋₆ fluoroalkyl, —C₁₋₆alkyl-OH, —(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₉ cycloalkyl,—(CH₂)_(r)—C₁₋₆ fluoroalkyl, —(CH₂)_(s)—O—C₁₋₆ fluoroalkyl, phenyl,heteroaryl, heterocyclyl, —(CH₂)_(t)-phenyl, or —(CH₂)_(v)-heteroaryl,wherein each phenyl and heteroaryl is optionally substituted with one tothree identical or different R^(c) groups; and additionally, R₃ and R₄,together with the carbon atom carrying them, may form a C₃₋₉ cycloalkylgroup.

In one embodiment, R³ and R⁴ are identical or different and are ahydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, —(CH₂)_(q)—C₃₋₉ cycloalkyl,phenyl, heteroaryl, a heterocyclyl group, —(CH₂)_(t)-phenyl, or—(CH₂)_(v)-heteroaryl, wherein each phenyl and heteroaryl is optionallysubstituted with one to three identical or different R^(c) groups.

In one embodiment, R³ and R⁴, together with the carbon atom carryingthem, form a C₃₋₉ cycloalkyl group.

In one embodiment, R³ and R⁴, together with the carbon atom carryingthem, form a cyclopentyl group or a cyclohexyl group.

The Group R³

In one embodiment, R³ is a hydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl,—(CH₂)_(q)—C₃₋₉ cycloalkyl, phenyl, heteroaryl, heterocyclyl,—(CH₂)_(t)-phenyl, or —(CH₂)_(v)-heteroaryl, wherein each phenyl andheteroaryl is optionally substituted with one to three identical ordifferent R^(c) groups.

In one embodiment, R³ is a hydrogen atom, C₁₋₈ alkyl, C₃₋₇ cycloalkyl,—(CH₂)_(q)—C₃₋₇ cycloalkyl, phenyl, heteroaryl, heterocyclyl,—(CH₂)_(t)-phenyl, or —(CH₂)_(v)-heteroaryl, wherein each phenyl andheteroaryl is optionally substituted with one to three identical ordifferent R^(c) groups.

In one embodiment, R³ is a hydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl,or phenyl, wherein phenyl is optionally substituted with one to threeidentical or different R^(c) groups.

In one embodiment, R³ is a hydrogen atom, C₁₋₈ alkyl, C₃₋₇ cycloalkyl,or phenyl, wherein phenyl is optionally substituted with one to threeidentical or different R^(c) groups.

In one embodiment, R³ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or phenyl, whereinphenyl is optionally substituted with one to three identical ordifferent R^(c) groups.

In one embodiment, R³ is a hydrogen atom, C₁₋₈ alkyl, C₃₋₇ cycloalkyl,or phenyl.

In one embodiment, R³ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, or phenyl.

In one embodiment, R³ is a hydrogen atom.

In one embodiment, R³ is C₁₋₈ alkyl.

In one embodiment, R³ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl,heptyl, or isoheptyl.

In one embodiment, R³ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, or tert-butyl.

In one embodiment, R³ is methyl, ethyl, propyl, isopropyl, butyl, orisobutyl.

In one embodiment, R³ is methyl, ethyl, propyl, or isopropyl.

In one embodiment, R³ is methyl or ethyl.

In one embodiment, R³ is methyl.

In one embodiment, R³ is C₃₋₇ cycloalkyl.

In one embodiment, R³ is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

In one embodiment, R³ is cyclopropyl, cyclobutyl, or cyclopentyl.

In one embodiment, R³ is phenyl optionally substituted with one to threeidentical or different R^(c) groups.

In one embodiment, R³ is phenyl.

The Group R⁴

In one embodiment, R⁴ is C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, —C₁₋₆ alkyl-OH,—(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₉ cycloalkyl, phenyl, or—(CH₂)_(t)-phenyl, wherein each phenyl is optionally substituted withone to three identical or different R^(c) groups.

In one embodiment, R⁴ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, —C₁₋₆ alkyl-OH,—(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₇ cycloalkyl, phenyl, or—(CH₂)_(t)-phenyl, wherein each phenyl is optionally substituted withone to three identical or different R^(c) groups.

In one embodiment, R⁴ is C₁₋₈ alkyl, C₃₋₇ cycloalkyl, —C₁₋₆ alkyl-OH, or—(CH₂)_(t)-phenyl, wherein phenyl is optionally substituted with one tothree identical or different R^(c) groups.

In one embodiment, R⁴ is C₁₋₈ alkyl.

In one embodiment, R⁴ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl,heptyl, or isoheptyl.

In one embodiment, R⁴ is C₃₋₈ alkyl.

In one embodiment, R⁴ is propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, or isoheptyl.

In one embodiment, R⁴ is propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, or isohexyl.

In one embodiment, R⁴ is propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, or isopentyl.

In one embodiment, R⁴ is propyl or isopropyl.

In one embodiment, R⁴ is butyl, isobutyl, sec-butyl, or tert-butyl.

In one embodiment, R⁴ is butyl or isobutyl.

In one embodiment, R⁴ is isobutyl.

In one embodiment, R⁴ is pentyl or isopentyl.

In one embodiment, R⁴ isopentyl.

In one embodiment, R⁴ is C₃₋₇ cycloalkyl.

In one embodiment, R⁴ is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

In one embodiment, R⁴ is cyclopropyl, cyclobutyl, or cyclopentyl.

In one embodiment, R⁴ is phenyl, wherein phenyl is optionallysubstituted with one to three identical or different R^(c) groups.

The Groups R^(a), R^(b), and R^(d)

The groups R^(a), R^(b), and R^(d) appear in the groups COR^(a),COR^(b), and COR^(d).

In one embodiment, R^(a), R^(b), and R^(d), if present, are identical ordifferent and are C₁₋₆ alkyl, C₁₋₆ alkyloxy, or NR⁷R⁸.

In one embodiment, R^(a), if present, is C₁₋₆ alkyl.

In one embodiment, R^(a), if present, is C₁₋₆ alkyloxy.

In one embodiment, R^(a), if present, is NR⁷R⁸.

In one embodiment, R^(b), if present, is C₁₋₆ alkyl.

In one embodiment, R^(b), if present, is C₁₋₆ alkyloxy.

In one embodiment, R^(b), if present, is NR⁷R⁸.

In one embodiment, R^(d), if present, is C₁₋₆ alkyl.

In one embodiment, R^(d), if present, is C₁₋₆ alkyloxy.

In one embodiment, R^(d), if present, is NR⁷R⁸.

The Group R^(c)

The group R^(c) appears as an optional substituent on phenyl andheteroaryl.

In one embodiment, each R^(c), if present, is identical or different andis C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(u)—C₁₋₆ alkyl,C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆ alkyl-OH, COR^(d), CN, NO₂,NR⁹R¹⁰, OH, or a halogen atom.

In one embodiment, each R^(c), if present, is identical or different andis C₁₋₆ alkyl, C₁₋₆ alkyloxy, —S(O)_(u)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,C₁₋₆ fluoroalkyloxy, C₁₋₆ alkyl-OH, COR^(d), NR⁹R¹⁰, OH, or a halogenatom.

In one embodiment, each R^(c), if present, is identical or different andis C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, OH,or a halogen atom.

In one embodiment, each R^(c), if present, is identical or different andis C₁₋₆ alkyl, C₁₋₆ alkyloxy, OH, or a halogen atom.

In one embodiment, each R^(c), if present, is identical or different andis methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, OH, a fluorine atom, a chlorine atom, or abromine atom.

In one embodiment, each R^(c), if present, is identical or different andis methyl, ethyl, methoxy, ethoxy, propoxy, OH, a fluorine atom, achlorine atom, or a bromine atom.

The Groups R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹ and R¹⁰

The groups R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹ and R¹⁰ appear in thegroups NR⁵R⁶, NR^(5′)R^(6′), NR⁷R⁸, and NR⁹R¹⁰.

In one embodiment, R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹ and R¹⁰, ifpresent, are identical or different and are a hydrogen atom, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, or —(CH₂)_(w)—C₃₋₇ cycloalkyl;

-   -   and additionally, R⁵ and R⁶, together with the nitrogen atom        carrying them, may form a heterocyclyl group;    -   and additionally, R^(5′) and R^(6′), together with the nitrogen        atom carrying them, may form a heterocyclyl group;    -   and additionally, R⁷ and R⁸, together with the nitrogen atom        carrying them, may form a heterocyclyl group;    -   and additionally, R⁹ and R¹⁰, together with the nitrogen atom        carrying them, may form a heterocyclyl group.

In one embodiment, R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹ and R¹⁰, ifpresent, are identical or different

-   -   and are a hydrogen atom, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or        —(CH₂)_(w)—C₃₋₇ cycloalkyl;    -   and additionally, R⁵ and R⁶, together with the nitrogen atom        carrying them, may form azetidinyl, pyrolidinyl, piperidinyl,        azepanyl, morpholinyl, or piperazinyl;    -   and additionally, R^(5′) and R^(6′), together with the nitrogen        atom carrying them, may form azetidinyl, pyrolidinyl,        piperidinyl azepanyl, morpholinyl, or piperazinyl;    -   and additionally, R⁷ and R⁸, together with the nitrogen atom        carrying them, may form azetidinyl, pyrolidinyl, piperidinyl,        azepanyl, morpholinyl, or piperazinyl;    -   and additionally, R⁹ and R¹⁰, together with the nitrogen atom        carrying them, may form azetidinyl, pyrolidinyl, piperidinyl,        azepanyl, morpholinyl, or piperazinyl.

The Indices i, i, k, l, p, q, r, s, t, v, and w

The indices i, j, k, l, p, q, r, s, t, v, and w appear in the groups—(CH₂)_(i)—, —(CH₂)_(j)—, —(CH₂)_(k)—, —(CH₂)_(l)—, —(CH₂)_(p)—,—(CH₂)_(q)—, —(CH₂)_(r)—, —(CH₂)_(s)—, —(CH₂)_(t)—, —(CH₂)_(v)—, and—(CH₂)_(w)—.

In one embodiment, i, j, k, l, p, q, r, s, t, v, and w, if present, aredifferent or identical and are 1, 2 or 3.

In one embodiment, i, j, k, l, p, q, r, s, t, v, and w, if present, aredifferent or identical and are 1 or 2.

In one embodiment, i, if present, is 1.

In one embodiment, i, if present, is 2.

In one embodiment, i, if present, is 3.

In one embodiment, j, if present, is 1.

In one embodiment, j, if present, is 2.

In one embodiment, j, if present, is 3.

In one embodiment, k, if present, is 1.

In one embodiment, k, if present, is 2.

In one embodiment, k, if present, is 3.

In one embodiment, l, if present, is 1.

In one embodiment, l, if present, is 2.

In one embodiment, l, if present, is 3.

In one embodiment, p, if present, is 1.

In one embodiment, p, if present, is 2.

In one embodiment, p, if present, is 3.

In one embodiment, q, if present, is 1.

In one embodiment, q, if present, is 2.

In one embodiment, q, if present, is 3.

In one embodiment, r, if present, is 1.

In one embodiment, r, if present, is 2.

In one embodiment, r, if present, is 3.

In one embodiment, s, if present, is 1.

In one embodiment, s, if present, is 2.

In one embodiment, s, if present, is 3.

In one embodiment, t, if present, is 1.

In one embodiment, t, if present, is 2.

In one embodiment, t, if present, is 3.

In one embodiment, v, if present, is 1.

In one embodiment, v, if present, is 2.

In one embodiment, v, if present, is 3.

In one embodiment, w, if present, is 1.

In one embodiment, w, if present, is 2.

In one embodiment, w, if present, is 3.

The Indices m, n, and u

The indices m, n, and u appear in the groups —S(O)_(m)—, —S(O)_(n)—, and—S(O)_(u)—.

In one embodiment, m, if present, is 0.

In one embodiment, m, if present, is 1.

In one embodiment, m, if present, is 2.

In one embodiment, n, if present, is 0.

In one embodiment, n, if present, is 1.

In one embodiment, n, if present, is 2.

In one embodiment, u, if present, is 0.

In one embodiment, u, if present, is 1.

In one embodiment, u, if present, is 2.

Configuration

If R³ and R⁴ are different, then the carbon atom to which R³ and R⁴ areattached is chiral, and may be in the (S) configuration or the (R)configuration.

In one embodiment, if R³ and R⁴ are different, then the carbon atom towhich R³ and R⁴ are attached is in the (S) configuration.

In one embodiment, if R³ and R⁴ are different, then the carbon atom towhich R³ and R⁴ are attached is in the (R) configuration.

Specific Compounds

In one embodiment, the compound is a compound selected from thefollowing compounds, or a pharmaceutically acceptable salt, hydrate, orsolvate thereof:

Compound No. Name Structure 1 2-Hydroxy-2- methyl- pentanoic acid(2-bromo-pyridin- 4-yl)-amide

2 2-Ethyl-2-hydroxy- 5-methyl- hexanoic acid (2-bromo-pyridin-4-yl)-amide

3 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-2-(4- methoxy-phenyl)-propionamide

4 2-Hydroxy-2,4- dimethyl- pentanoic acid (2-bromo-pyridin- 4-yl)-amide

5 2-Ethyl-2- hydroxy-hexanoic acid (2-bromo- 6-methoxy-pyridin-4-yl)-amide

6 2-Hydroxy-2- propyl-pentanoic acid (2-bromo- pyridin-4-yl)-amide

7 N-(2-Bromo- pyridin-4-yl)-2- cyclohexyl-2- hydroxy- butyramide

8 2-Hydroxy-2- methyl-hexanoic acid (2-bromo- 6-methoxy-pyridin-4-yl)-amide

9 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-cyclopentyl- 2-hydroxy-butyramide

10 N-(2-Bromo- pyridin-4-yl)- 2-hydroxy-2- (2-methoxy- phenyl)-propionamide

11 2-Hydroxy-2- methyl-pentanoic acid (2,6-dimethoxy- pyrimidin-4-yl)-amide

12 2-Hydroxy-2- methyl-octanoic acid (2-bromo-6- methoxy-pyridin-4-yl)-amide

13 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-ethyl-2- hydroxy-3-methyl-butyramide

14 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-2-methyl- propionamide

15 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-2-methyl- butyramide

16 2-Ethyl-2-hydroxy- 4-methyl- pentanoic acid (2- bromo-6-methoxy-pyridin-4-yl)-amide

17 N-(2-Bromo- pyridin-4-yl)-2- cyclopentyl-2- hydroxy- propionamide

18 2-Hydroxy-2- methyl- heptanoic acid (2- bromo-6-methoxy-pyridin-4-yl)-amide

19 2-Ethyl-2- hydroxy-pentanoic acid (2-bromo-6- methoxy-pyridin-4-yl)-amide

20 2-Hydroxy-2,4- dimethyl-pentanoic acid (2-methoxy-pyridin-4-yl)-amide

21 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-cyclopentyl- 2-hydroxy-propionamide

22 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-ethyl-2- hydroxy- butyramide

23 2-Butyl-2- hydroxy-hexanoic acid (2-bromo- pyridin-4-yl)-amide

24 N-(2-Bromo-pyridin- 4-yl)-2-hydroxy-4- (4-methoxy- phenyl)-2-methyl-butyramide

25 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-hydroxy- 2,3-dimethyl-butyramide

26 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-hydroxy-2- methyl-4-phenyl-butyramide

27 2-(4-Fluoro-phenyl)- 2-hydroxy-N- (2-methoxy- pyridin-4-yl)-propionamide

28 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-4-(2- methoxy-phenyl)- 2-methyl-butyramide

29 2-Hydroxy-2- propyl-pentanoic acid (2-bromo-6- methoxy-pyridin-4-yl)-amide

30 3-(4-Fluoro-phenyl)- 2-hydroxy-N-(2- methoxy-pyridin- 4-yl)-2-methyl-propionamide

31 N-(2-Bromo- pyridin-4-yl)-2- ethyl-2-hydroxy- butyramide

32 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-2-phenyl- propionamide

33 N-(2-Bromo-pyridin- 4-yl)-2-hydroxy- 2-methyl-3-phenyl- propionamide

34 2-Hydroxy-2- methyl-heptanoic acid (2-bromo- pyridin-4-yl)-amide

35 N-(2-Bromo-pyridin- 4-yl)-2-hydroxy-2- (3-methoxy-phenyl)-propionamide

36 2-Ethyl-2- hydroxy-pentanoic acid (2-methoxy- pyridin-4-yl)-amide

37 N-(2-Bromo- pyridin-4-yl)-2- hydroxy-4-(3- methoxy-phenyl)- 2-methyl-butyramide

38 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-hydroxy-2- methyl-propionamide

39 2-Hydroxy-2- methyl-pentanoic acid (2-methoxy- pyridin-4-yl)-amide

40 2-Hydroxy-2- methyl-octanoic acid (2-bromo- pyridin-4-yl)-amide

41 2-Hydroxy-2,4- dimethyl-pentanoic acid (2-bromo-6- methoxy-pyridin-4-yl)-amide

42 2-Hydroxy-2- methyl-hexanoic acid (2-bromo-6- methyl-pyridin-4-yl)-amide

43 N-(2-Bromo-pyridin- 4-yl)-2-hydroxy- 2-methyl-4-phenyl- butyramide

44 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-hydroxy- 2-phenyl-propionamide

45 2-Hydroxy-2- methyl-hexanoic acid (2-bromo- pyridin-4-yl)-amide

46 2-Ethyl-2- hydroxy-pentanoic acid (2-bromo- pyridin-4-yl)-amide

47 N-(2-Bromo-pyridin- 4-yl)-2-(4-fluoro- phenyl)-2-hydroxy- butyramide

48 2-Ethyl-2-hydroxy- 4-methyl-pentanoic acid (2-bromo-pyridin-4-yl)-amide

49 2-Ethyl-2-hydroxy- hexanoic acid (2- bromo-pyridin-4- yl)-amide

50 2-Hydroxy-2- methyl-pentanoic acid (2- trifluoromethyl-pyridin-4-yl)-amide

51 N-(2-Bromo- pyridin-4-yl)-2- cyclopentyl-2- hydroxy-butyramide

52 2-Ethyl-2,6- dihydroxy-hexanoic acid (2-bromo- pyridin-4-yl)-amide

53 2-Hydroxy-2,4- dimethyl-pentanoic acid (2-cyano-6- methoxy-pyridin-4-yl)-amide

54 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-hydroxy- propionamide

55 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-hydroxy- butyramide

56 N-(2-Bromo-6- methoxy-pyrimidin- 4-yl)-2-ethyl-2- hydroxy- butyramide

57 1-Hydroxy- cyclopentanecarboxylic acid (2-bromo- pyridin-4-yl)-amide

58 1-Hydroxy- cyclohexanecarboxylic acid (2-bromo- pyridin-4-yl)-amide

59 4-(2-Hydroxy-2- methyl- pentanoylamino)- pyridine-2-carboxylic acidmethyl ester

60 2-Hydroxy-2- methyl-pentanoic acid (2-bromo-6- methoxy-pyridin-4-yl)-amide

61 2-Hydroxy-2-methyl- pentanoic acid (6- bromo-2-oxo-1,2-dihydro-pyridin-4-yl)- amide (see note below)

62 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-hydroxy- 2-methyl-butyramide

63 2-Hydroxy-hexanoic acid (2-bromo-6- methoxy-pyridin- 4-yl)-amide

64 (and 65) 2-Hydroxy-2- isopropyl-pentanoic acid (2-bromo-6-methoxy-pyridin- 4-yl)-amide

66 2-Butyl-2-hydroxy- hexanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide

67 N-(2-Bromo-6- methoxy-pyridin-4-yl)- 2,2-dicyclopentyl-2-hydroxy-acetamide

68 N-(2-Bromo-6- methoxy-pyridin-4- yl)-2-hydroxy- 2-isopropyl-3-methyl-butyramide

69 N-(2-Bromo-6- methoxy-pyridin- 4-yl)-2-hydroxy- 2-(tetrahydro-pyran-4-yl)-propionamide

70 2-Hydroxy-2-propyl- hexanoic acid (2- bromo-6-methoxy-pyridin-4-yl)-amide

Note: Compound 61 is named and drawn above as a 1H-pyridin-2-one, thatis, as the tautomer of 2-hydroxy-2-methyl-pentanoic acid(6-bromo-2-hydroxy-pyridin-4-yl)-amide. As discussed below, and unlessotherwise specified, it is intended that a reference to one tautomerencompasses all tautomers.

In one embodiment, the compound is a compound selected from thefollowing compounds, or a pharmaceutically acceptable salt, hydrate, orsolvate thereof:

Compound No. Name Structure 81 N-(2-Bromo-6-methoxy- pyridin-4-yl)-2-cyclopropyl-2- hydroxy-propionamide

82 N-(2-Bromo-6-methoxy- pyridin-4-yl)-2- cyclopropyl-2-hydroxy-butyramide

83 N-(2-Bromo-6-methoxy- pyridin-4-yl)-2-cyclobutyl-2-hydroxy-butyramide

84 N-(2-Bromo-6-methoxy- pyridin-4-yl)-2,2- dicyclopropyl-2-hydroxy-acetamide

85 N-(2-Bromo-6- methoxy-pyridin-4-yl)- 2,2-dicyclobutyl-2-hydroxy-acetamide

86 2-Cyclopropyl-2- hydroxy-pentanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide

87 2-Cyclopropyl-2- hydroxy-4-methyl- pentanoic acid (2-bromo-6-methoxy- pyridin-4-yl)-amide

88 2-Cyclobutyl-2- hydroxy-4-methyl- pentanoic acid (2- bromo-6-methoxy-pyridin-4-yl)-amide

89 2-Hydroxy-2,4-dimethyl- pentanoic acid (2,6- dimethoxy-pyridin-4-yl)-amide

In one embodiment, the compound is the following compound, or apharmaceutically acceptable salt, hydrate, or solvate thereof:

Com- pound No. Name Structure 41 2-Hydroxy-2,4- dimethyl- pentanoic acid(2-bromo-6- methoxy-pyridin- 4-yl)-amide

In one embodiment, the compound is the following compound, or apharmaceutically acceptable salt, hydrate, or solvate thereof:

Com- pound No. Name Structure 71A (R)-2-Hydroxy- 2,4-dimethyl- pentanoicacid (2-bromo-6- methoxy-pyridin- 4-yl)-amide

In one embodiment, the compound is the following compound, or apharmaceutically acceptable salt, hydrate, or solvate thereof:

Com- pound No. Name Structure 71B (S)-2-Hydroxy- 2,4-dimethyl- pentanoicacid (2-bromo-6- methoxy-pyridin- 4-yl)-amide

Combinations

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³, R⁴, R⁵, R^(5′), R⁶, R^(6′), R⁷, R⁸, R⁹, R¹⁰, R^(a), R^(b),R^(c), R^(d), X, i, j, k, l, m, n, p, q, r, s, t, u, v, w, etc.) arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterised, and tested for biological activity). In addition, allsub-combinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentinvention and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

Substantially Purified Forms

One aspect of the present invention pertains to certainN-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides, as described herein,in substantially purified form and/or in a form substantially free fromcontaminants.

In one embodiment, the compound is in substantially purified form and/orin a form substantially free from contaminants.

In one embodiment, the compound is in a substantially purified form witha purity of least 50% by weight, e.g., at least 60% by weight, e.g., atleast 70% by weight, e.g., at least 80% by weight, e.g., at least 90% byweight, e.g., at least 95% by weight, e.g., at least 97% by weight,e.g., at least 98% by weight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compoundin any stereoisomeric or enantiomeric form. For example, in oneembodiment, the substantially purified form refers to a mixture ofstereoisomers, i.e., purified with respect to other compounds. In oneembodiment, the substantially purified form refers to one stereoisomer,e.g., optically pure stereoisomer. In one embodiment, the substantiallypurified form refers to a mixture of enantiomers. In one embodiment, thesubstantially purified form refers to an equimolar mixture ofenantiomers (i.e., a racemic mixture, a racemate). In one embodiment,the substantially purified form refers to one enantiomer, e.g.,optically pure enantiomer.

In one embodiment, the compound is in a form substantially free fromcontaminants wherein the contaminants represent no more than 50% byweight, e.g., no more than 40% by weight, e.g., no more than 30% byweight, e.g., no more than 20% by weight, e.g., no more than 10% byweight, e.g., no more than 5% by weight, e.g., no more than 3% byweight, e.g., no more than 2% by weight, e.g., no more than 1% byweight.

Unless specified, the contaminants refer to other compounds, that is,other than stereoisomers or enantiomers. In one embodiment, thecontaminants refer to other compounds and other stereoisomers. In oneembodiment, the contaminants refer to other compounds and the otherenantiomer.

In one embodiment, the compound is in a substantially purified form withan optical purity of at least 60% (i.e., 60% of the compound, on a molarbasis, is the desired stereoisomer or enantiomer, and 40% is undesiredstereoisomer(s) or enantiomer), e.g., at least 70%, e.g., at least 80%,e.g., at least 90%, e.g., at least 95%, e.g., at least 97%, e.g., atleast 98%, e.g., at least 99%.

Isomers

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diastereoisomeric, epimeric, atropic,stereoisomeric, tautomeric, conformational, or anomeric forms, includingbut not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, andr-forms; endo- and exo-forms; R—, S—, and meso-forms; D- and L-forms; d-and I-forms; (+) and (−) forms; keto-, enol-, and enolate-forms; syn-and anti-forms; synclinal- and anticlinal-forms; α- and 3-forms; axialand equatorial forms; boat-, chair-, twist-, envelope-, andhalfchair-forms; and combinations thereof, hereinafter collectivelyreferred to as “isomers” (or “isomeric forms”).

For example, the N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amidesdescribed herein may have one or more chiral carbon atoms. Suchcompounds may therefore exist in the form of a particular enantiomer ordisastereoisomer, or a mixture of enantiomers or diastereoisomers. Theseenantiomers and diastereoisomers, as well as their mixtures, includingthe racemic mixtures, form part of the invention.

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₈alkyl includesn-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

For example, 1H-pyridin-2-one and 2-hydroxy-pyridine are tautomers (asshown below).

For example, Compound 61 is named and drawn above as a 1H-pyridin-2-one,that is, as the tautomer of 2-hydroxy-2-methyl-pentanoic acid(6-bromo-2-hydroxy-pyridin-4-yl)-amide. Unless otherwise specified, itis intended that a reference to one tautomer encompasses all tautomers.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including mixtures (e.g., racemicmixtures) thereof. Methods for the preparation (e.g., asymmetricsynthesis) and separation (e.g., fractional crystallisation andchromatographic means) of such isomeric forms are either known in theart or are readily obtained by adapting the methods taught herein, orknown methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous. Examples of suitable organicanions include, but are not limited to, those derived from the followingorganic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic,ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic,hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic,lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic,oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic,propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric,toluenesulfonic, and valeric. Examples of suitable polymeric organicanions include, but are not limited to, those derived from the followingpolymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound alsoincludes salt forms thereof.

For example, the N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amidesdescribed herein may exist in the base state or state of addition saltswith acids. Such addition salts form part of the invention. These saltsmay be advantageously prepared with pharmaceutically acceptable acids,but the salts of other useful acids, for example those used for thepurification or isolation of the compounds may also be used, and alsoform part of the invention. These acids may be, for example,hydrochloric acid or nitric acid. For a review of physiologicallyacceptable salts see the Handbook of Pharmaceutical Salts: Properties,Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Solvates and Hydrates

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the compound. The term “solvate” is used hereinin the conventional sense to refer to a complex of solute (e.g.,compound, salt of compound) and solvent. If the solvent is water, thesolvate may be conveniently referred to as a hydrate, for example, ahemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

For example, the solvates and/or hydrates may be obtained directly atthe end of the synthesis process, with the target compound beingisolated in the form of a hydrate, for example a mono- or hemi-hydrate,or in the form of a solvate of the reaction solvent and/or purificationsolvent.

Unless otherwise specified, a reference to a particular compound alsoincludes solvate (e.g., hydrate) forms thereof.

Typical procedures for making and identifying suitable hydrates andsolvates are well known to those in the art; see for example, pages202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York,1999.

Hydrates and solvates can be isolated and characterized by methods knownin the art, such as, thermogravimetric analysis (TGA), TGA-massspectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction(XRPD), Karl Fisher titration, high resolution X-ray diffraction, andthe like. There are several commercial entities that provide quick andefficient services for identifying solvates and hydrates on a routinebasis.

For the avoidance of doubt, it is understood that the phrase“pharmaceutically acceptable salts and solvates thereof” and the phrase“pharmaceutically acceptable salt or solvate thereof” embracepharmaceutically acceptable solvates (e.g., hydrates) of the compounds,pharmaceutically acceptable salts of the compounds, as well aspharmaceutically acceptable solvates (e.g., hydrates) ofpharmaceutically acceptable salts of the compounds.

Chemical Synthesis

Methods for the chemical synthesis of the N-(pyrid-4-yl)amides andN-(pyrimidin-4-yl)amides (as described herein) are described herein.These and/or other well-known methods may be modified and/or adapted inknown ways in order to facilitate the synthesis of additionalN-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides (as described herein).

Compounds of formula (1) may be prepared, for example, by the methodsdescribed in Scheme 1 and Scheme 2 below.

In one approach, compounds of formula (1) may be prepared from anintermediate of the ketoamide type of formula (IV), by reaction with anorganometallic derivative such as an organomagnesium compound (R4MgY) oran organolithium compound (R4Li) in a solvent such as, for example,tetrahydrofuran, according to Method 1a illustrated in Scheme 1.

The intermediaries of the ketoamide type of formula (IV) may be preparedby a peptidic coupling reaction between a ketoacid of formula (II) andan amine of formula (III) in the presence of a coupling agent, forexample, but not limited to, dicyclohexylcarbodiimide by analogy, forexample, to the reactions described in Bodansky, M., Synthesis (1972),pp. 453-463. Amines of formula (III) are commercially available and/ormay be prepared according to methods well known to the person skilled inthe art.

In another approach, compounds of formula (1) may be prepared by areaction between an acid of formula (V), activated in the form of anacyl chloride by means, for example, of oxalyl chloride or thionylchloride, and an amine of formula (III), in the presence of a base suchas triethylamine and in a solvent such as tetrahydrofuran, for example,according to Method 1b illustrated in Scheme 1.

The acid compounds of formula (V) are commercially available and/or canbe prepared, for example, from ketoacids of formula (II) by reactionwith an organometallic derivative such as an organomagnesium compound(R4MgY) or an organolithium compound (R4Li) in a solvent such as, forexample, tetrahydrofuran, according to Scheme 3. The ketoacids offormula (II) are commercially available compounds and/or may be preparedaccording to methods well known to the person skilled in the art.

In another approach, compounds of formula (1) may be prepared by areaction between an acid of formula (V) and a compound of the sulfinylamine type of formula (X) in a solvent such as toluene, for example,according to Method 1c illustrated in Scheme 1 and by analogy, forexample, to the reactions described in Hee Kim Yong et al., TetrahedronLetters, (1985), pp. 3821-3824.

The compounds of the type sulfinyl amine of formula (X) may be preparedfrom amines of formula (III) by reaction, for example, with thionylchloride, as described in Hee Kim Yong et al., Tetrahedron Letters,(1985), pp. 3821-3824 or Hanson et al., J. Chem. Soc. Perkin Trans. 1,(1990), pp. 2089-2097.

In another approach, compounds of formula (1) may also be prepared bythe reaction of an organometallic derivative such as an organomagnesiumcompound (R4MgZ) or an organolithium compound (R4Li) and a ketoamideintermediate of formula (IV) according to Method 1d illustrated inScheme 2 and by analogy, for example, with the reactions described inGrimm et al., Bioorganic & Medicinal Chemistry, (2003), pp. 4133-4141.

The ketoamide derivatives of formula (IX) may be prepared by thereaction of an intermediary N-methoxy N-methyl oxalamide, of formula(VIII) and an organometallic derivative such as an organomagnesiumcompound (R4MgZ) or an organolithium compound (R4Li) in a solvent suchas tetrahydrofuran (THF), for example.

The intermediates N-methoxy N-methyl oxalamide of formula (VIII) may beprepared by peptidic coupling between an acid intermediary of formula(VII) and O,N-dimethylhydroxylamine in the presence of a coupling agent,for example, and not limited to, O-benzotriazolyl tetramethylisouroniumtetrafluoroborate (TBTU), in the presence of a base such as triethylamine (TEA), for example, in a solvent such as tetrahydrofuran, forexample, and by analogy, for example, with the reactions described inGillessen, D., Tetrahedron Letters, (1989) pp. 1927-1930.

The acid intermediates of formula (VII) may be obtained by hydrolysis ofthe intermediate of formula (VI), for example by means of aqueous sodiumhydroxide.

The intermediates of formula (VI) may be obtained by peptidic couplingbetween amines of formula (III) and ethyl oxalate chloride in thepresence of a base such as triethylamine, for example, in a solvent suchas tetrahydrofuran, for example.

Compositions

Another aspect of the present invention pertains to a composition (e.g.,a pharmaceutical composition; a physiologically acceptable composition;a cosmetic composition) comprising an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein, and a carrier, diluent, orexcipient (e.g., a pharmaceutically acceptable carrier, diluent, orexcipient; a physiologically acceptable carrier, diluent, or excipient;a cosmetic carrier, diluent, or excipient).

Another aspect of the present invention pertains to a method ofpreparing a composition (e.g., a pharmaceutical composition; aphysiologically acceptable composition; a cosmetic composition)comprising mixing an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, asdescribed herein, and a carrier, diluent, or excipient (e.g., apharmaceutically acceptable carrier, diluent, or excipient; aphysiologically acceptable carrier, diluent, or excipient; a cosmeticcarrier, diluent, or excipient).

Uses

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides, as describedherein, are useful, for example, in the treatment of disorders anddiseases that are ameliorated by the inhibition of an androgen receptor,as described herein.

Use in Methods of Modulating (e.q., Inhibiting) an Androgen Receptor

Another aspect of the present invention pertains to a method ofmodulating (e.g., inhibiting) an androgen receptor, in vitro or in vivo,comprising contacting the androgen receptor with an effective amount ofan N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein.

Another aspect of the present invention pertains to a method ofmodulating (e.g., inhibiting) an androgen receptor in a cell, in vitroor in vivo, comprising contacting the cell with an effective amount ofan N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein.

Suitable assays for determining androgen receptor modulation (e.g.,inhibition) are described herein and/or are known in the art.

In one embodiment, the method is performed in vitro.

In one embodiment, the method is performed in vivo.

In one embodiment, the N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide isprovided in the form of a pharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, skin,adipose, lung, gastrointestinal (including, e.g., bowel, colon), breast(mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder,pancreas, and brain.

One of ordinary skill in the art is readily able to determine whether ornot a candidate compound modulates (e.g., inhibits) an androgenreceptor. For example, suitable assays are described herein.

Use in Methods of Therapy

Another aspect of the present invention pertains to anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a method of treatment of the human or animal body by therapy.

Use in the Manufacture of Medicaments

Another aspect of the present invention pertains to use of anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, inthe manufacture of a medicament for use in treatment.

In one embodiment, the medicament comprises the N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide.

Methods of Treatment

Another aspect of the present invention pertains to a method oftreatment comprising administering to a patient in need of treatment atherapeutically effective amount of an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein, preferably in the form ofa pharmaceutical composition.

Diseases and Disorders Ameliorated by the Modulation (e.g., Inhibition)of an Androgen Receptor

Compounds that modulate (e.g., inhibit) an androgen receptor, forexample, androgen receptor agonists and androgen receptor antagonists,are useful in the treatment of, for example, various hormone-dependentdiseases and disorders (e.g., androgen-dependent diseases anddisorders).

In one embodiment (e.g., of use in methods of therapy, of use in themanufacture of medicaments, of methods of treatment), the treatment istreatment of a disease or disorder that is ameliorated by the modulation(e.g., inhibition) of an androgen receptor.

In one embodiment, the treatment is treatment of an androgen-dependentdisease or disorder.

Dermatological Diseases and Disorders

A number of dermatological diseases and disorders may be treated withcompounds that modulate (e.g., inhibit) an androgen receptor.

In one embodiment, the treatment is treatment of a dermatologicaldisease or disorder; a disease or disorder of the sebaceous gland(s);acne; hyperseborrhoea; oily skin; seborrhoeic dermatitis; hyperpilosityor hirsutism; atopic dermatitis; or androgenic alopecia.

In one embodiment, the treatment is treatment of a dermatologicaldisease or disorder.

In one embodiment, the treatment is treatment of a disease or disorderof the sebaceous gland(s).

In one embodiment, the treatment is treatment of acne.

In one embodiment, the treatment is treatment of hyperseborrhoea.

In one embodiment, the treatment is treatment of oily skin.

In one embodiment, the treatment is treatment of seborrhoeic dermatitis.

In one embodiment, the treatment is treatment of hyperpilosity orhirsutism.

In one embodiment, the treatment is treatment of atopic dermatitis.

In one embodiment, the treatment is treatment of androgenic alopecia.

Additional Hormone-Dependent Diseases and Disorders

In one embodiment, the treatment is treatment of a hormone-dependentcancer, such as prostate or breast cancer.

In one embodiment, the treatment is treatment of a benign hyperplasia ofthe prostate gland, premature puberty, virilisation, polycystic ovarysyndrome, Stein-Lelventhal syndrome, loss of libido, or endometriosis.

In one embodiment, the treatment is treatment of loss of muscular mass(sarcopaenia), muscular atrophy, impotence, masculine sterility,abnormal masculine differentiation (hermaphrodism), hypogonadism, orosteoporosis.

Treatment

The term “treatment,” as used herein in the context of treating adisorder, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the disorder, and includes a reduction in the rate ofprogress, a halt in the rate of progress, alleviation of symptoms of thedisorder, amelioration of the disorder, and cure of the disorder.Treatment as a prophylactic measure (i.e., prophylaxis) is alsoincluded. For example, use with patients who have not yet developed thedisorder, but who are at risk of developing the disorder, is encompassedby the term “treatment.”

For example, treatment includes the prophylaxis of acne, reducing theincidence of acne, alleviating the symptoms of acne, etc.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of a compound, or a material, composition or dosage formcomprising a compound, which is effective for producing some desiredtherapeutic effect, commensurate with a reasonable benefit/risk ratio,when administered in accordance with a desired treatment regimen.

Combination Therapies

The term “treatment” includes combination treatments and therapies, inwhich two or more treatments or therapies are combined, for example,sequentially or simultaneously. For example, the compounds describedherein may also be used in combination therapies, e.g., in conjunctionwith other agents.

One aspect of the present invention pertains to a compound as describedherein, in combination with one or more (e.g., 1, 2, 3, 4, etc.)additional therapeutic agents, as described below.

The particular combination would be at the discretion of the physicianwho would select dosages using his common general knowledge and dosingregimens known to a skilled practitioner.

The agents (i.e., the compound described herein, plus one or more otheragents) may be administered simultaneously or sequentially, and may beadministered in individually varying dose schedules and via differentroutes. For example, when administered sequentially, the agents can beadministered at closely spaced intervals (e.g., over a period of 5-10minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart,or even longer periods apart where required), the precise dosage regimenbeing commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more otheragents) may be formulated together in a single dosage form, oralternatively, the individual agents may be formulated separately andpresented together in the form of a kit, optionally with instructionsfor their use.

For example, the N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amidesdescribed herein may be used alone or in combination, for example, oneor more of:

-   -   an antibiotic product, such as erythromycin or fusidic acid;    -   azelaic acid or a derivative thereof;    -   a retinoid or retinoid derivative for the treatment of acne,        such as tretinoin, adapalene, or tazarolene;    -   an inhibitor of 5α-reductase, such as (5α,        17β)-N-1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene-17-carboxamide        (also known as finasteride, Proscar, and Propecia);    -   an androgen receptor blocking agent for the treatment of acne,        alopecia or hirsutism;    -   a product stimulating the growth of hair or for the treatment of        alopecia, such as 6-piperidin-1-ylpyrimidine-2,4-diamine 3-oxide        (also known as minoxidil).

Non-Therapeutic and Cosmetic Uses

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides, as describedherein, are also useful in the field of cosmetics, especially in bodycare and hair care, and more especially for the treatment of skin withan acneic tendency.

Another aspect of the present invention pertains to a physiologicallyacceptable composition (e.g., a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, anda physiologically acceptable carrier, diluent, or excipient (e.g., acosmetic carrier, diluent, or excipient).

The terms “physiologically acceptable” and “cosmetic,” as used herein,pertains to compounds, ingredients, materials, compositions, dosageforms, etc., which are, within the scope of sound medical judgment,suitable for cosmetic use in contact with the tissues (e.g., skin, hair,nails, mucosa, etc.) of the subject in question (e.g., human) withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. Eachphysiologically acceptable (e.g., cosmetic) carrier, diluent, excipient,etc. must also be “acceptable” in the sense that it is compatible withthe other ingredients of the formulation.

The physiologically acceptable composition (e.g., cosmetic composition)is a composition compatible with the skin and, as necessary, with itsappendages (lashes, nails, hair) and/or mucous membranes.

The physiologically acceptable composition (e.g., cosmetic composition)may be in the form of, for example, an ointment, a cream, a milk, apomade, a gel, a suspension (e.g., a microsphere or nanospheresuspension), lipidic or polymeric blisters or polymeric or gelledpatches allowing controlled release, a powder, a lipidic or polymericblister, an alcohol swab, a syndet, a solution, a spray, a mousse, astick, a soap, a cleansing base, or a shampoo.

The concentration of the N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amidein the physiologically acceptable composition (e.g., cosmeticcomposition) is preferably between 0.001% and 3% by weight relative tothe total weight of the composition.

Another aspect of the present invention pertains to a non-therapeuticmethod (e.g., a cosmetic method) of body care and/or hair carecomprising applying to a subject's body and/or hair an effective amountof an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as describedherein, preferably in the form of a physiologically acceptablecomposition (e.g., a cosmetic composition).

Another aspect of the present invention pertains to use of anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, ina non-therapeutic method (e.g., a cosmetic method) of body care and/orhair care.

Another aspect of the present invention pertains to anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a non-therapeutic method (e.g., a cosmetic method) of body careand/or hair care.

Another aspect of the present invention pertains to use of anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, inthe manufacture of physiologically acceptable composition (e.g., acosmetic composition) for use in a non-therapeutic method of body careand/or hair care.

Another aspect of the present invention pertains to a non-therapeuticmethod (e.g., a cosmetic method) of body care and/or hair care,comprising applying to the body and/or hair of a subject an effectiveamount of a physiologically acceptable composition (e.g., a cosmeticcomposition) comprising an N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein.

Another aspect of the present invention pertains to use of aphysiologically acceptable composition (e.g., a cosmetic composition)comprising an N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, asdescribed herein in a non-therapeutic method (e.g., a cosmetic method)of body care and/or hair care.

Another aspect of the present invention pertains to a physiologicallyacceptable composition (e.g., a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein, foruse in a non-therapeutic method (e.g., a cosmetic method) of body careand/or hair care.

Other Uses

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides described hereinmay also be used as cell culture additives to modulate (e.g., inhibit)an androgen receptor, etc.

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides described hereinmay also be used as part of an in vitro assay, for example, in order todetermine whether a candidate host is likely to benefit from treatmentwith the compound in question.

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides described hereinmay also be used as a standard, for example, in an assay, in order toidentify other active compounds, other modulators (e.g., inhibitors) ofan androgen receptor, etc.

Kits

Another aspect of the invention pertains to a kit comprising (a) anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide as described herein, or acomposition (e.g., a pharmaceutical composition; a physiologicallyacceptable composition; a cosmetic composition) comprising anN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide as described herein,e.g., preferably provided in a suitable container and/or with suitablepackaging; and (b) instructions for use, e.g., written instructions onhow to administer the compound or composition.

The written instructions may also include a list of indications forwhich the active ingredient is a suitable treatment.

Routes of Administration

The N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide or pharmaceuticalcomposition comprising the N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide may be administered to a subject by anyconvenient route of administration, whether systemically/peripherally ortopically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

In some preferred embodiments, the compound or composition isadministered transdermally and/or transmucosally, e.g., to skin and/ormucous membrane of the subject/patient.

For such embodiments, the compound or composition may suitable beapplied in the form of an ointment, a cream, a milk, a pomade, a gel, asuspension (e.g., a microsphere or nanosphere suspension), lipidic orpolymeric blisters or polymeric or gelled patches allowing controlledrelease, a powder, a lipidic or polymeric blister, an alcohol swab, asyndet, a solution, a spray, a mousse, a stick, a soap, a cleansingbase, or a shampoo.

For such embodiments, the compound is present in the composition at aconcentration generally ranging from 0.001% to 30% by weight, andpreferably from 0.01% to 10% by weight, relative to the total weight ofthe composition.

The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, aplacental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g.,a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), alagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog),feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig),ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., amonkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g.,gorilla, chimpanzee, orangutang, gibbon), or a human.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the compound to be administered alone, it ispreferable to present it as a pharmaceutical formulation (e.g.,composition, preparation, medicament) comprising at least oneN-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, as described herein,together with one or more other pharmaceutically acceptable ingredientswell known to those skilled in the art, including, but not limited to,pharmaceutically acceptable carriers, diluents, excipients, adjuvants,fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers,solubilisers, surfactants (e.g., wetting agents), masking agents,colouring agents, flavouring agents, and sweetening agents. Theformulation may further comprise other active agents, for example, othertherapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising mixing at least one N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, as described herein, together with one or moreother pharmaceutically acceptable ingredients well known to thoseskilled in the art, e.g., carriers, diluents, excipients, etc. Ifformulated as discrete units (e.g., tablets, etc.), each unit contains apredetermined amount (dosage) of the compound.

The term “pharmaceutically acceptable,” as used herein, pertains tocompounds, ingredients, materials, compositions, dosage forms, etc.,which are, within the scope of sound medical judgment, suitable for usein contact with the tissues of the subject in question (e.g., human)without excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio. Each carrier, diluent, excipient, etc. must also be “acceptable”in the sense of being compatible with the other ingredients of theformulation.

Suitable carriers, diluents, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbookof Pharmaceutical Excipients, 5th edition, 2005.

The formulations may be prepared by any methods well known in the art ofpharmacy. Such methods include the step of bringing into association thecompound with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the compound with carriers (e.g.,liquid carriers, finely divided solid carrier, etc.), and then shapingthe product, if necessary.

The formulation may be prepared to provide for rapid or slow release;immediate, delayed, timed, or sustained release; or a combinationthereof.

Formulations may suitably be in the form of liquids, solutions (e.g.,aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous)(including, e.g., microsphere and nanosphere suspensions), emulsions(e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries,mouthwashes, drops, tablets (including, e.g., coated tablets), granules,powders, losenges, pastilles, capsules (including, e.g., hard and softgelatin capsules), cachets, pills, ampoules, boluses, suppositories,pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils,foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster,bandage, dressing, or the like which is impregnated with one or morecompounds and optionally one or more other pharmaceutically acceptableingredients, including, for example, penetration, permeation, andabsorption enhancers. Formulations may also suitably be provided in theform of a depot or reservoir.

The compound may be dissolved in, suspended in, or mixed with one ormore other pharmaceutically acceptable ingredients. The compound may bepresented in a liposome or other microparticulate which is designed totarget the compound, for example, to blood components or one or moreorgans.

Formulations suitable for oral administration (e.g., by ingestion)include liquids, solutions (e.g., aqueous, non-aqueous), suspensions(e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water,water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders,capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes,losenges, pastilles, as well as patches, adhesive plasters, depots, andreservoirs. Losenges typically comprise the compound in a flavoredbasis, usually sucrose and acacia or tragacanth. Pastilles typicallycomprise the compound in an inert matrix, such as gelatin and glycerin,or sucrose and acacia. Mouthwashes typically comprise the compound in asuitable liquid carrier.

Formulations suitable for sublingual administration include tablets,losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),mouthwashes, losenges, pastilles, as well as patches, adhesive plasters,depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration includeliquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g.,aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),suppositories, pessaries, gels, pastes, ointments, creams, lotions,oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels,pastes, ointments, creams, lotions, and oils, as well as patches,adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine thecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g., povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g., lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc, silica);disintegrants (e.g., sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g., sodium lauryl sulfate);preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid); flavours, flavour enhancing agents, and sweeteners.Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the compound therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with acoating, for example, to affect release, for example an enteric coating,to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or awater-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example, at least about 30% w/w of a polyhydric alcohol, i.e., analcohol having two or more hydroxyl groups such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycoland mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the compoundthrough the skin or other affected areas. Examples of such dermalpenetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase,which may optionally comprise merely an emulsifier (otherwise known asan emulgent), or it may comprise a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. Preferably, ahydrophilic emulsifier is included together with a lipophilic emulsifierwhich acts as a stabiliser. It is also preferred to include both an oiland a fat. Together, the emulsifier(s) with or without stabiliser(s)make up the so-called emulsifying wax, and the wax together with the oiland/or fat make up the so-called emulsifying ointment base which formsthe oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulfate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or other mineral oils canbe used.

Formulations suitable for intranasal administration, where the carrieris a liquid, include, for example, nasal spray, nasal drops, or byaerosol administration by nebuliser, include aqueous or oily solutionsof the compound.

Formulations suitable for intranasal administration, where the carrieris a solid, include, for example, those presented as a coarse powderhaving a particle size, for example, in the range of about 20 to about500 microns which is administered in the manner in which snuff is taken,i.e., by rapid inhalation through the nasal passage from a container ofthe powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalationor insufflation therapy) include those presented as an aerosol sprayfrom a pressurised pack, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye dropswherein the compound is dissolved or suspended in a suitable carrier,especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols, for example,cocoa butter or a salicylate; or as a solution or suspension fortreatment by enema.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the compound, such carriers as are known inthe art to be appropriate.

Formulations suitable for parenteral administration (e.g., byinjection), include aqueous or non-aqueous, isotonic, pyrogen-free,sterile liquids (e.g., solutions, suspensions), in which the compound isdissolved, suspended, or otherwise provided (e.g., in a liposome orother microparticulate). Such liquids may additionally contain otherpharmaceutically acceptable ingredients, such as anti-oxidants, buffers,preservatives, stabilisers, bacteriostats, suspending agents, thickeningagents, and solutes which render the formulation isotonic with the blood(or other relevant bodily fluid) of the intended recipient. Examples ofexcipients include, for example, water, alcohols, polyols, glycerol,vegetable oils, and the like. Examples of suitable isotonic carriers foruse in such formulations include Sodium Chloride Injection, Ringer'sSolution, or Lactated Ringer's Injection. Typically, the concentrationof the compound in the liquid is from about 1 ng/mL to about μg/mL, forexample from about 10 ng/mL to about 1 μg/mL. The formulations may bepresented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriatedosages of the N-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide, andcompositions comprising the N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, can vary from patient to patient. Determiningthe optimal dosage will generally involve the balancing of the level oftherapeutic benefit against any risk or deleterious side effects. Theselected dosage level will depend on a variety of factors including, butnot limited to, the activity of the particular N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, the route of administration, the time ofadministration, the rate of excretion of the N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide, the duration of the treatment, other drugs,compounds, and/or materials used in combination, the severity of thedisorder, and the species, sex, age, weight, condition, general health,and prior medical history of the patient. The amount of-(pyrid-4-yl)amide or N-(pyrimidin-4-yl)amide and route ofadministration will ultimately be at the discretion of the physician,veterinarian, or clinician, although generally the dosage will beselected to achieve local concentrations at the site of action whichachieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration can be effected in one dose, continuously orintermittently (e.g., in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell(s) being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician, veterinarian, or clinician.

In general, a suitable dose of the N-(pyrid-4-yl)amide orN-(pyrimidin-4-yl)amide is in the range of about 10 μg to about 250 mg(more typically about 100 μg to about 25 mg) per kilogram body weight ofthe subject per day. Where the compound is a salt, an ester, an amide, aprodrug, or the like, the amount administered is calculated on the basisof the parent compound and so the actual weight to be used is increasedproportionately.

EXAMPLES

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

Chemical Synthesis Synthesis 1 2-Hydroxy-2-methyl-pentanoic acid(2-bromo-pyridin-4-yl)-amide (Compound 1) Preparation According toScheme 1, Method 1a Step 1.1 N-(2-bromo-pyridin-4-yl)-2-oxo-propionamide

2.8 g (32.2 mmol, 2 eq) of pyruvic acid (initial product 1) were pouredinto a 50 mL single collar flask, 20 mL of thionyl was added to this andit was heated at reflux for 2 hours. After 2 hours, the reaction mixturewas dry concentrated by azeotroping several times with dry toluene. 2.8g (16.1 mmol, 1 eq) of 2-bromo-pyridin-4-ylamine (initial product 2),diluted in 5 mL of pyridine, was then added, drop-by-drop at 0° C., andthe mixture agitated at ambient temperature for 16 hours. The reactionmixture was diluted with 50 mL of ethyl acetate, washed with 50 mL of anaqueous solution of saturated sodium bicarbonate, followed by 3×50 mL ofwater. The organic phase was dry concentrated. The residue waschromatographed on silica with a heptanes/ethyl acetate mixture (2/1v/v) as eluent. N-(2-bromo-pyridin-4-yl)-2-oxo-propionamide was obtainedin the form of a white solid.

Step 1.2 2-Hydroxy-2-methyl-pentanoic acid (2-bromo-pyridin-4-yl)-amide

170 mg (0.70 mmol, 1 eq) of N-(2-bromo-pyridin-4-yl)-2-oxo-propionamidewas poured into a three-collar flask and 5 mL of tetrahydrofuran addedand the mixture cooled to 0° C. 1.1 mL (2.0 mmol, 3 eq) of a solution ofmagnesium bromide magnesium (initial product 3) (2 M) was added to thetetrahydrofuran drop-by-drop and agitated for 1 hour and 30 minutes atambient temperature. The reaction mixture was cooled to 0° C. and 25 mLof an aqueous solution of hydrochloric acid (1 M) was added. The organicphases were extracted with 2×50 mL of ethyl acetate, washed with 2×50 mLof water, dried over magnesium sulphate, and dry concentrated. A yellowoil was obtained which was chromatographed on silica with aheptanes/ethyl acetate mixture (1/1 v/v) as eluent.2-hydroxy-2-methyl-pentanoic acid (2-bromo-pyridin-4-yl)-amide wasobtained in the form of a white solid.

Melting point=102° C. NMR (¹H, DMSO): 0.82-0.86 (t; 3H; J=8 Hz);1.14-1.17 (m; 1H); 1.41 (s; 3H)1.41-1.44 (m; 1H); 1.49-156 (m; 1H);1.67-1.70 (m; 1H) 5.74 (s; 1H); 7.81-7.83 (d; 1H; J=8 HZ); 8.13 (s; 1H);8.21-8.23 (d; 1H; J=8 Hz); 10.15 (s; 1H).

Syntheses 2 to 51

Syntheses 2 to 51 are described in Table 1 below. The compounds weresynthesised according to the above procedure by replacing the initialproducts 1, 2 and 3 referred to in Synthesis 1 by the initial productsmentioned in Table 1. In the context of the ¹H NMR data shown in Table1, s=singlet, d=doublet, t=triplet, m=multiplet, q=quartet, J=couplingconstant in hertz (Hz).

TABLE 1 Melting Cmpd. Chemical Initial Initial Initial point ¹H NMR No.Name Product 1 Product 2 Product 3 (° C.) 400 Mhz 2 2-Ethyl-2- Keto2-Bromo- Magnesium Oil (DMSO) hydroxy-5- butyric pyridin-4- isopentyl0.84-0.78 (m, 9H); methyl- acid ylamine bromide 0.9-1.0 (m, 1H);hexanoic acid 1.3-1.5 (m, 2H); (2-bromo- 1.5-1.6 (m, 2H); 1.7pyridin-4-yl)- 1.8 (m, 2H); 5.5 (s, amide 1H); 7.8 (dd, 1H, J = 1.8 Hz);8.1 (d, 1H, J = 1.7 Hz); 8.2 (d, 1H, J = 5.6 Hz); 10.1 (s, 1H) 3N-(2-Bromo- Pyruvic 2-Bromo- 4-methoxy- 66 (DMSO) 1.68 (s,pyridin-4-yl)-2- acid pyridin-4- phenyl 3H); 3.72 (s, 3H); hydroxy-2-(4-ylamine magnesium 6.55 (s, 1H); methoxy- bromide 6.9 (m, 2H); 7.49 (m,phenyl)- 2H); 7.79 (dd, 1H, propionamide J = 1.8 Hz); 8.09 (d, 1H, J =1.7 Hz); 8.19 (d, 1H, J = 5.6 Hz); 10.3 (s, 1H) 4 2-Hydroxy-2,4- Pyruvic2-Bromo- Magnesium oil (DMSO) 0.78 (m, dimethyl- acid pyridin-4-isobutyl 3H); 0.90 (m, 3H); pentanoic acid ylamine chloride 1.33 (s,3H); (2-bromo- 1.45-1.55 (m, 1H); pyridin-4-yl)- 1.7-1.8 (m, 2H); amide5.7 (s, 1H); 7.82 (dd, 1H, J = 1.8 Hz); 8.13 (d, 1H, J = 1.7 Hz); 8.22(d, 1H, J = 5.6 Hz); 10.2 (s, 1H) 5 2-Ethyl-2- Keto 2-Bromo-6- Magnesium101 (DMSO) hydroxy- butyric methoxy- n-butyl 0.77-0.85 (m, 6 H),hexanoic acid acid pyridin-4- bromide 1.0-1.1 (m, 1 H), (2-bromo-6-ylamine 1.20-1.25 (m, 2 H), methoxy- 1.32-1.57 (m, 3 pyridin-4-yl)- H),1.68-1.77 (m, amide 2 H), 3.80 (s, 3 H), 5.46 (s, 1 H), 7.33 (d, 1 H, J= 1.5 Hz), 7.74 (d, 1 H, J = 1.5 Hz), 10.01 (1 H, s) 6 2-Hydroxy-2-2-Oxo 2-Bromo- Magnesium oil (DMSO) 0.83 (t, propyl- pentanoicpyridin-4- propyl 6H, J = 7.2 Hz); pentanoic acid acid ylamine bromide1.07-1.11 (m, 2H); (2-bromo- 1.43-1.54 (m, 4H); pyridin-4-yl)- 1.67-1.71(m, 2H); amide 5.5 (s, 1H); 7.82 (dd, 1H, J = 1.8 Hz), 8.13 (d, 1H, J =1.7 Hz); 8.21 (d, 1H, J = 5.6 Hz); 10.1 (s, 1H) 7 N-(2-Bromo- Keto2-Bromo- Magnesium oil (DMSO) 0.78 (t, pyridin-4-yl)-2- butyricpyridin-4- cyclohexyl 3H, J = 7.3 Hz); cyclohexyl-2- acid ylaminebromide 1.0-1.25 (m, 5H); hydroxy- 1.35-1.45 (m, 1H); butyramide1.55-1.85 (m, 7H); 5.3 (s, 1H); 7.8 (d, 1H, J = 1.7 Hz); 8.14 (d, 1H, J= 1.7 Hz); 8.21 (d, 1H, J = 5.6 Hz); 10 (s, 1H) 8 2-Hydroxy-2- Pyruvic2-Bromo-6- Magnesium 98 (CHCl₃) methyl- acid methoxy- n-butyl 0.89-092(t, 3H, J = 7.1 Hz), hexanoic acid pyridin-4- chloride 1.19-1.45 (m,4H), (2-bromo-6- ylamine 1.51 (s, 3H), methoxy- 1.60-1.68 (m, 1H),pyridin-4-yl)- 1.93-2.0 (m, 1H), amide 3.93 (s, 3H), 7.03 (d, 1H), 7.36(d, 1H), 8.82 (s, 1H) 9 N-(2-Bromo-6- Keto 2-Bromo-6- Magnesium Not(DMSO) 0.8 (t; methoxy- butyric methoxy- cyclopentyl determined 3H; J =8 Hz); pyridin-4-yl)-2- acid pyridin-4- bromide 1.4-1.6 (m; 9H);cyclopentyl-2- ylamine 1.8 (m; 1H); 2.2 (m; hydroxy- 1H); 3.8 (s; 3H);butyramide 5.3 (s; 1H); 7.3 (d; 1H; J = 1.4 Hz); 7.7 (d; 1H; J = 1.4Hz); 10.0 (s; 1H) 10 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium 63 (DMSO)1.66 (s, pyridin-4-yl)-2- acid pyridin-4- 2-methoxy- 3H); 3.61 (s, 3H);hydroxy-2-(2- ylamine phenyl 6.05 (s, 1H); methoxy- bromide 6.96-6.99(m, 2H); phenyl)- 7.28-7.32 (m, 1H); propionamide 7.51 (m, 1H); 7.79(dd, 1H, J = 1.8 Hz); 8.08 (d, 1H, J = 1.7 Hz); 8.20 (d, 1H, J = 5.6Hz); 10.1 (s, 1H) 11 2-Hydroxy-2- Pyruvic 2,6- Magnesium 147 (DMSO) 0.9(t; methyl- acid Dimethoxy- propyl 3H; J = 8 Hz); pentanoic acidpyrimidin-4- bromide 1.0-1.2 (m; 1H); (2,6-dimethoxy- ylamine 1.3 (s;3H); pyrimidin-4-yl)- 1.4-1.5 (m; 1H); amide 1.5-1.6 (m; 1H); 1.7 (m;1H); 3.86 (s; 3H); 3.88 (s; 3H); 6.0 (s; 1H) 7.1 (s; 1H); 9.4 (s; 1H) 122-Hydroxy-2- Pyruvic 2-Bromo-6- Magnesium oil (DMSO) 0.83 (t,methyl-octanoic acid methoxy- n-hexyl 3H, J = 7.0 Hz); acid (2-bromo-pyridin-4- bromide 1.05-1.15 (m, 1H); 6-methoxy- ylamine 1.2-1.3 (m,6H); pyridin-4-yl)- 1.3 (s, 3H); amide 1.35-1.45 (m, 1H); 1.5-1.6 (m,1H); 1.65-1.75 (m, 1H); 3.8 (s, 3H); 5.7 (s, 1H); 7.32 (d, 1H, J = 1.4Hz); 7.73 (d, 1H, J = 1.4 Hz); 10.1 (s, 1H) 13 N-(2-Bromo-6- Keto2-Bromo-6- Magnesium 114 (DMSO) methoxy- butyric methoxy- isopropyl0.76-0.80 (m, 6H), pyridin-4-yl)-2- acid pyridin-4- bromide 0.87-0.88(d, 3H, J = 6.8 Hz), ethyl-2- ylamine 1.58-1.78 (m, hydroxy-3- 2H),1.9-2.0 (m, methyl- 1H), 3.80 (s, 3H), butyramide 5.30 (s, 1H), 7.33 (d,1H, J = 1.5 Hz), 7.74 (d, 1H, J = 1.5 Hz), 9.98 (1 H, s) 14 N-(2-Bromo-Pyruvic 2-Bromo- Magnesium 150 (CDCl₃) 1.5 (s; pyridin-4-yl)-2- acidpyridin-4- methyl 6H); 2.6 (s; 1H); hydroxy-2- ylamine iodide 7.4 (dd;1H; J = 5.6, methyl- 1.8 Hz); 7.85 (s; propionamide 1H); 8.2 (d; 1H; J =5.6 Hz) 15 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium 108 (CDCl₃) 0.9 (t;3H; pyridin-4-yl)-2- acid pyridin-4- ethyl J = 8 Hz); 1.5 (s; hydroxy-2-ylamine bromide 3H); 1.6-1.7 (m; methyl- 1H); 1.9-2.0 (m; butyramide1H); 7.4 (d; 1H; J = 4 Hz); 7.8 (s; 1H); 8.2 (d; 1H; J = 4 Hz); 8.8 (s;1H) 16 2-Ethyl-2- Keto 2-Bromo-6- Magnesium 114 (DMSO) hydroxy-4-butyric methoxy- isobutyl 0.73-0.79 (m, 6H), methyl- acid pyridin-4-bromide 0.89-0.91 (d, 3H, J = 6.4 Hz), pentanoic acid ylamine 1.43-1.53(m, (2-bromo-6- 2H), 1.68-1.77 (m, methoxy- 3H), 3.80 (s, 3 H),pyridin-4-yl)- 5.46 (s, 1 H), amide 7.34 (d, 1 H, J = 1.5 Hz), 7.74 (d,1 H, J = 1.5 Hz), 10.08 (1 H, s). 17 N-(2-Bromo- Pyruvic 2-Bromo-Magnesium oil (DMSO) 1.32 (s, pyridin-4-yl)-2- acid pyridin-4-cyclopentyl 3H); 1.39-1.53 (m, cyclopentyl-2- ylamine bromide 8H); 2.2(m, 1H); hydroxy- 5.76 (s, 1H); propionamide 7.82 (q, 1H, J = 1.8 Hz);8.13 (d, 1H, J = 1.7 Hz); 8.22 (d, 1H, J = 5.6 Hz); 10.2 (s, 1H) 182-Hydroxy-2- Pyruvic 2-Bromo-6- Magnesium 81 (DMSO) 0.83 (t, methyl-acid methoxy- n-pentyl 3H, J = 7.1 Hz); heptanoic acid pyridin-4-bromide 1.17-125 (m, 5H); (2-bromo-6- ylamine 1.31 (s, 3H); methoxy-1.35-1.45 (m, 1H); pyridin-4-yl)- 1.50-1.55 (m, 1H); amide 1.65-1.75 (m,1H); 3.8 (s, 3H); 5.71 (s, 1H); 7.32 (d, 1H, J = 1.4 Hz); 7.73 (d, 1H, J= 1.4 Hz); 10.1 (s, 1H) 19 2-Ethyl-2- Keto 2-Bromo-6- Magnesium 79(DMSO) hydroxy- butyric methoxy- propyl 0.62-0.70 (6 H, m), pentanoicacid acid pyridin-4- bromide 0.85-1.0 (1 H, m), (2-bromo-6- ylamine1.31-1.41 (3 H, m), methoxy- 1.52-1.60 (2H, pyridin-4-yl)- m), 3.65 (3H, s), amide 5.35 (1 H, s), 7.18 (1 H, d, J = 1.5 Hz), 7.59 (1 H, d, J =1.5 Hz), 9.90 (1H, S). 20 2-Hydroxy-2,4- Pyruvic 2-Methoxy- Magnesium135 (DMSO) 0.8 (d; dimethyl- acid pyridin-4- isobutyl 3H; J = 8 Hz);pentanoic acid ylamine bromide 0.9 (d; 3H; J = 8 Hz); (2-methoxy- 1.3(s; 3H); pyridin-4-yl)- 1.5 (m; 1H); amide 1.7-1.8 (m; 2H); 3.8 (s; 3H);5.7 (s; 1H); 7.3 (s; 1H); 7.4 (d; 1H; J = 6 Hz); 8.0 (d; 1H; J = 6 Hz);9.9 (s; 1H) 21 N-(2-Bromo-6- Pyruvic 2-Bromo-6- Magnesium n/d (DMSO) 1.3(s; methoxy- acid methoxy- cyclopentyl 3H); 1.4-1.6 (m; pyridin-4-yl)-2-pyridin-4- bromide 3H); 2.2 (m; 1H); cyclopentyl-2- ylamine 3.8 (s; 3H);5.7 (s; hydroxy- 1H); 7.3 (d; 1H; propionamide J = 1.4 Hz); 7.7 (d; 1H;J = 1.4 Hz); 10.1 (s; 1H) 22 N-(2-Bromo-6- Keto 2-Bromo-6- Magnesium 123(DMSO) methoxy- butyric methoxy- ethyl 0.78-0.81 (t, 6 H, J = 7.4 Hz),pyridin-4-yl)-2- acid pyridin-4- bromide 1.52-1.57 (m, ethyl-2- ylamine2 H), hydroxy- 1.71-1.76 (m, 2 H), 3.80 (s, butyramide 3 H), 5.44 (s, 1H), 7.33 (d, 1 H, J = 1.5 Hz), 7.74 (d, 1 H, J = 1.5 Hz), 10.02 (1 H,s). 23 2-Butyl-2- 2-aceto 2-Bromo- Magnesium oil (DMSO) 0.82 (t,hydroxy- hexanoic pyridin-4- n-butyl 6H, J = 7.4 Hz); hexanoic acid acidylamine bromide 1.0-1.1 (m, 2H); (2-bromo- 1.22 (m, 4H); pyridin-4-yl)-1.35-1.4 (m, 2H); amide 1.5-1.55 (m, 2H); 1.7-1.8 (m, 2H); 5.49 (s, 1H);7.8 (s, 1H); 8.13 (d, 1H, J = 1.6 Hz); 8.21 (d, 1H, J = 5.6 Hz); 10.1(s, 1H) 24 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium oil (DMSO) 1.37 (s,pyridin-4-yl)-2- acid pyridin-4- 4-methoxy- 3H); 1.75-1.85 (m,hydroxy-4-(4- ylamine phenyl 1H); 1.95-2.05 (m, methoxy- methyl 1H);2.35-2.45 (m, phenyl)-2- 1H); 2.6 2.7 (m, methyl- 1H); 3.68 (s, 3H);butyramide 6.0 (m, 1H); 6.79 (m, 2H); 7.07 (m, 2H); 7.81 (dd, 1H, J =1.8 Hz); 8.12 (d, 1H, J = 1.7 Hz); 8.22 (d, 1H, J = 5.6 Hz); 10.2 (s,1H) 25 N-(2-Bromo-6- Pyruvic 2-Bromo-6- Magnesium 152 (CDCl₃) methoxy-acid methoxy- isopropyl 0.92-0.93 (d, 3 H, J = 6.9 Hz), pyridin-4-yl)-2-pyridin-4- bromide 0.99-1.00 (d, hydroxy-2,3- ylamine 3 H, J = 6.9 Hz),dimethyl- 1.48 (s, 3 H), butyramide 1.93 (s, 1 H), 2.15-2.18 (m, 1 H),3.93 (s, 3 H), 7.02 (d, 1 H, J = 1.5 Hz), 7.36 (d, 1 H, J = 1.5 Hz),8.78 (s, 1 H) 26 N-(2-Bromo-6- Pyruvic 2-Bromo-6- Magnesium oil (CDCl₃)1.56 (s, methoxy- acid methoxy- phenethyl 3H), 1.94, 2.0 (m,pyridin-4-yl)-2- pyridin-4- chloride 1 H), hydroxy-2- ylamine 2.31-2.39(m, 1 H), methyl-4- 2.62-2.65 (m, 1 H), phenyl- 2.75-2.79 (m, 1butyramide H), 3.94 (s, 3 H), 7.02 (d, 1 H, J = 1.5 Hz), 7.18-7.35 (m, 5H), 7.36 (d, 1 H, J = 1.5 Hz), 8.80 (1 H, s) 27 2-(4-Fluoro- Pyruvic2-Methoxy- Magnesium 175 (DMSO) 1.7 (s; phenyl)-2- acid pyridin-4- 4-3H); 3.8 (s; 3H); hydroxy-N-(2- ylamine fluorophenyl 6.7 (s; 1H);methoxy- bromide 7.2 (Tr; 2H; J = 8 Hz); pyridin-4-yl)- 7.3 (s; 1H); 7.4(d; propionamide 1H; J = 8 Hz); 7.6 (m; 2H); 8.0 (d; 1H; J = 8 Hz); 10.1(s; 1H) 28 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium oil (DMSO) 1.38 (s,pyridin-4-yl)-2- acid pyridin-4- 2-methoxy- 3H); 1.77-1.78 (m,hydroxy-4-(2- ylamine phenyl ethyl 1H); 1.96-1.97 (m, methoxy- bromide1H); 2.41-2.42 (m, phenyl)-2- 1H); 2.71-2.72 (m, methyl- 1H); 3.73 (s,3H); butyramide 5.88 (s, 1H); 6.8-6.84 (m, 1H); 6.89-6.91 (d, 1H, J =8.1 Hz); 7.08 (dd, 1H, J = 1.5 Hz); 7.12-7.16 (m, 1H); 7.82 (dd, 1H, J =1.8 Hz); 29 2-Hydroxy-2- 2-Oxo 2-Bromo-6- Magnesium oil (DMSO) 0.8 (t;propyl- pentanoic methyl- propyl 6H; J = 8 Hz); pentanoic acid acidpyridin-4- chloride 1.1 (m; 2H); (2-bromo-6- ylamine 1.4-1.5 (m; 2H);1.7 (m; methoxy- 2H); 3.8 (s; 3H); pyridin-4-yl)- 5.5 (s; 1H); 7.3 (d;amide 1H; J = 1.4 Hz); 7.7 (d; 1H; J = 1.4 Hz); 10 (s; 1H) 303-(4-Fluoro- Pyruvic 2-Methoxy- Magnesium 175 (DMSO) 1.3 (s; phenyl)-2-acid pyridin-4- 4- 3H); 2.8 (d; 1H; hydroxy-N-(2- ylamine fluorophenyl J= 13.4); 3.0 (d; methoxy- bromide 1H; J = 13.4 Hz); pyridin-4-yl)-2- 3.8(s; 3H); 5.9 (s; methyl- 1H); 7.1 (t; 2H; propionamide J = 9 Hz); 7.2(m; 3H); 7.3 (m; 1H); 8.0 (d; 1H; J = 6 Hz) 9.7 (s; 1H) 31 N-(2-Bromo-Keto 2-Bromo- Magnesium oil (CDCl₃) 1.0 (t; 6H; pyridin-4-yl)-2- butyricpyridin-4- ethyl J = 4 Hz); ethyl-2- acid ylamine bromide 1.6-1.7 (m;2H); hydroxy- 2.0-2.1 (m; 2H); 7.5 (d; butyramide 1H; J = 6 Hz); 7.9 (s;1H); 8.3 (d; 1H; J = 6 Hz); 8.9 (s; 1H) 32 N-(2-Bromo- Pyruvic 2-Bromo-Magnesium n/d (CDCl₃) 1.9 (s; pyridin-4-yl)-2- acid pyridin-4- phenyl3H); 3.0 (s; 1H); hydroxy-2- ylamine bromide 7.3-7.4 (m; 4H); phenyl-7.5 (m; 2H) 7.8 (s; propionamide 1H); 8.1 (d; 1H; J = 4 Hz); 8.8 (s; 1H)33 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium oil (DMSO) 1.34 (s,pyridin-4-yl)-2- acid pyridin-4- benzyl 3H); 2.85 (d, 1H, hydroxy-2-ylamine bromide J = 13.3 Hz); methyl-3- 3.03 (d, 1H, J = 13.3 hz);phenyl- 6.0 (m, 1H); propionamide 7.16-7.24 (m, 5H); 7.75 (dd, 1H, J =1.8 Hz); 8.05 (d, 1H, J = 1.8 Hz); 8.19 (d, 1H, J = 5.6 Hz); 10.1 (s,1H) 34 2-Hydroxy-2- Pyruvic 2-Bromo- Magnesium oil (DMSO) 0.83 (t,methyl- acid pyridin-4- n-pentyl 3H, J = 7 Hz); heptanoic acid ylaminebromide 1.10-1.27 (m, 5H); (2-bromo- 1.32 (s, 3H); pyridin-4-yl)-1.37-1.43 (m, 1H); amide 1.49-1.56 (m, 1H); 1.67-1.73 (m, 1H); 5.7 (s,1H); 7.82 (dd, 1H, J = 1.6 Hz); 8.12 (d, 1H, J = 1.4 Hz); 8.22 (d, 1H, J= 5.6 Hz); 10.2 (s, 1H) 35 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium oil(DMSO) 1.69 (s, pyridin-4-yl)-2- acid pyridin-4- 3-methoxy- 3H); 3.75(s, 3H); hydroxy-2-(3- ylamine pentyl 6.63 (s, 1H); methoxy- bromide6.83-6.86 (m, 1H); phenyl)- 7.1-7.2 (m, 2H); propionamide 7.26 (m, 1H);7.8 (dd, 1H, J = 1.8 Hz); 8.09 (d, 1H, J = 1.7 Hz); 8.19 (d, 1H, J = 5.6Hz); 10.4 (s, 1H) 36 2-Ethyl-2- Keto 2-Methoxy- Magnesium n/d (DMSO)hydroxy- butyric pyridin-4- propyl 0.8-0.9 (m; 6H); pentanoic acid acidylamine bromide 1.0-1.2 (m; 1H); (2-methoxy- 1.5-1.6 (m; 3H);pyridin-4-yl)- 1.7-1.8 (m; 2H); 5.4 (s; amide 1H); 7.3; (s; 1H); 7.4 (d;1H; J = 6 HZ); 8.0 (d; 1H; J = 6 Hz); 9.8 (s; 1H) 37 N-(2-Bromo- Pyruvic2-Bromo- Magnesium oil (DMSO) 1.38 (s, pyridin-4-yl)-2- acid pyridin-4-3-methoxy- 3H); 1.8-1.9 (m, hydroxy-4-(3- ylamine phenethyl 1H); 2.0 (m,1H); methoxy- bromide 2.7 (m, 1H); phenyl)-2- 3.7 (s, 3H); 6.0 (s,methyl- 1H); 6.72 (t, 3H, butyramide J = 1.1 Hz); 7.15 (m, 1H); 7.82(dd, 1H, J = 1.8 Hz); 8.12 (d, 1H, J = 1.7 Hz); 8.22 (d, 1H, J = 5.6Hz); 10.2 (s, 1H) 38 N-(2-Bromo-6- Pyruvic 2-Bromo-6- Magnesium 104(DMSO) 1.33 (s, 6 methoxy- acid methoxy- methyl H), 3.80 (s, 3 H),pyridin-4-yl)-2- pyridin-4- bromide 5.86 (s, 1 H), hydroxy-2- ylamine7.32 (d, 1 H, J = 1.5 Hz), methyl- 7.72 (d, 1 H, propionamide J = 1.Hz), 10.1 (1 H, s) 39 2-Hydroxy-2- Pyruvic 2-Methoxy- Magnesium 101(DMSO) 0.9 (t; methyl- acid pyridin-4- propyl 3H; J = 8 Hz); pentanoicacid ylamine bromide 1.1-1.2 (m; 1H); (2-methoxy- 1.3 (s; 1H);pyridin-4-yl)- 1.4-1.5 (m; 1H); amide 1.5-1.6 (m; 1H); 1.7 (m; 1H); 3.8(s; 3H); 5.7 (s; 1H); 7.3 (s; 1H); 7.4 (d; 1H; J = 6 Hz); 8.0 (d; 1H; J= 6 Hz); 9.9 (s; 1H) 40 2-Hydroxy-2- Pyruvic 2-Bromo- Magnesium oil(DMSO) 0.84 (m, methyl-octanoic acid pyridin-4- hexyl 3H,); acid(2-bromo- ylamine bromide 1.11-1.16 (m, 1H); pyridin-4-yl)- 1.21-1.26(m, 6H); 1.32 (s, amide 3H); 1.39-1.40 (m, 1H); 1.50-1.55 (m, 1H);1.67-1.71 (m, 1H); 5.7 (s, 1H); 7.82 (dd, 1H, J = 1.8 Hz); 8.12 (d, 1H,J = 1.7 Hz); 8.22 (d, 1H, J = 5.6 Hz); 10.1 (s, 1H) 41 2-Hydroxy-2,4-Pyruvic 2-Bromo-6- Magnesium 103 (DMSO) 0.77 (d, dimethyl- acid methoxy-isobutyl 3H, J = 6.4 Hz); pentanoic acid pyridin-4- chloride 0.89 (d,3H, (2-bromo-6- ylamine J = 6.5 Hz); 1.31 (s, methoxy- 3H); 1.45-1.5 (m,pyridin-4-yl)- 1H); 1.66-1.71 (m, amide 2H); 3.8 (s, 3H); 5.7 (s, 1H);7.33 (d, 1H, J = 1.4 Hz); 7.74 (d, 1H, J = 1.4 Hz); 10.1 (s, 1H) 422-Hydroxy-2- Pyruvic 2-Bromo-6- Magnesium oil (DMSO) 0.9 (t; methyl-acid methyl- n-butyl 3H; J = 8 Hz); hexanoic acid pyridin-4- bromide 1.1(m; 1H); (2-bromo-6- ylamine 1.2-1.3 (m; 2H); 1.32 (s; methyl-pyridin-3H); 1.33-1.41 (m; 4-yl)-amide 1H); 1.5-1.6 (m; 1H); 1.7 (m; 1H); 2.4(s; 3H); 5.7 (s; 1H); 7.7 (d; 1H; J = 1.4 Hz); 7.9 (d; 1H; J = 1.4 Hz));10.1 (s; 1H) 43 N-(2-Bromo- Pyruvic 2-Bromo- Magnesium oil (CDCl₃) 1.5(s; pyridin-4-yl)-2- acid pyridin-4- phenethyl 3H); 1.9 (m; 1H);hydroxy-2- ylamine chloride 2.2-2.3 (m; 1H); methyl-4- 2.6 (m; 1H);phenyl- 2.7 (m; 1H); 7.1 (m; butyramide 3H); 7.2 (m; 2H); 7.4 (d; 1H; J= 8 Hz); 7.8 (s; 1H); 8.2 (d; 1H; J = 8 Hz); 8.8 (s; 1H) 44N-(2-Bromo-6- Pyruvic 2-Bromo-6- Magnesium 161 (DMSO) 1.70 (s, 3methoxy- acid methoxy- phenyl H), 3.78 (s, 3 H), pyridin-4-yl)-2-pyridin-4- bromide 6.60 (s, 1H), hydroxy-2- ylamine 7.25-7.37 (m, 4 H),phenyl- 7.57-7.59 (m, 2 propionamide H), 7.71 (d, 1 H, J = 1.5 Hz). 452-Hydroxy-2- Pyruvic 2-Bromo- Magnesium oil (DMSO) 0.84 (t, methyl- acidpyridin-4- butyl 3H, J = 7.1 Hz); hexanoic acid ylamine chloride1.05-1.2 (m, 1H); (2-bromo- 1.21-1.27 (m, 2H); pyridin-4-yl)- 1.32 (s,3H); amide 1.4-1.5 (m, 1H); 1.5-1.55 (m, 1H); 1.7-1.75 (m, 1H); 5.7 (s,1H); 7.82 (dd, 1H, J = 1.8 Hz); 8.13 (d, 1H, J = 1.7 Hz); 8.22 (d, 1H, J= 5.6 Hz); 10.2 (s, 1H) 46 2-Ethyl-2- Keto 2-Bromo- Magnesium oil (DMSO)hydroxy- butyric pyridin-4- propyl 0.78-0.85 (m, 6H); pentanoic acidacid ylamine bromide 1.05-1.15 (m, 1H) (2-bromo- 1.4-1.6 (m, 3H);pyridin-4-yl)- 1.7-1.8 (m, 2H); 5.5 (s, amide 1H); 7.82 (dd, 1H, J = 1.8Hz); 8.13 (d, 1H, J = 1.7 Hz); 8.22 (q, 1H, J = 5.6 Hz); 10.0 (s, 1H) 47N-(2-Bromo- Keto 2-Bromo- Magnesium 55 (DMSO) 0.79 (t, pyridin-4-yl)-2-butyric pyridin-4- 4-fluoro- 3H, J = 7.2 Hz); (4-fluoro- acid ylaminephenyl 1.95-2.05 (m, 1H); phenyl)-2- bromide 2.2-2.3 (m, 1H); hydroxy-6.5 (s, 1H); butyramide 7.17 (t, 2H, J = 1.9 Hz); 7.60-7.63 (m, 2H); 7.8(dd, 1H, J = 1.8 Hz); 8.1 (d, 1H, J = 1.7 Hz); 8.2 (d, 1H, J = 5.6 Hz);10.4 (s, 1H) 48 2-Ethyl-2- Keto 2-Bromo- Magnesium oil (DMSO) hydroxy-4-butyric pyridin-4- isopropyl 0.7-0.8 (m, 6H); 0.91 (d, methyl- acidylamine bromide 3H, J = 6.4 Hz); pentanoic acid 1.45-1.6 (m, 2H);(2-bromo- 1.7-1.8 (m, 3H); pyridin-4-yl)- 5.45 (s, 1H); amide 7.8 (dd,1H, J = 1.8 Hz); 8.1 (d, 1H, J = 1.7 Hz); 8.2 (d, 1H, J = 5.6 Hz); 10.1(s, 1H) 49 2-Ethyl-2- Keto 2-Bromo- Magnesium oil (DMSO) hydroxy-butyric pyridin-4- n-butyl 0.80-0.85 (m, 6H); hexanoic acid acid ylaminechloride 1.03-1.09 (m, 1H); (2-bromo- 1.18-1.26 (m, 2H); pyridin-4-yl)-1.39-1.45 (m, 1H); amide 1.48-1.58 (m, 2H); 1.69-1.78 (m, 2H); 5.48 (s,1H); 7.82 (dd, 1H, J = 1.8 Hz); 8.14 (d, 1H, J = 1.7 Hz); 8.21 (d, 1H, J= 5.6 Hz); 10.1 (s, 1H) 50 2-Hydroxy-2- Pyruvic 2-Trifluoro Magnesium 98(CHCl₃) methyl- acid methyl- propyl 0.93-0.96 (t, 3 H, J = 7.3 Hz),pentanoic acid pyridin-4- chloride 1.26-1.32 (m, (2- ylamine 1 H),trifluoromethyl- 1.48-1.56 (m, 1H), 1.54 (s, 3 pyridin-4-yl)- H),1.62-1.69 (m, amide 1H), 1.93-2.01 (m, 1 H), 2.55 (s, 1 H), 7.73-7.75(dd, 1 H, J = 5.5. 2.1 Hz), 7.99 (d, 1 H, J = 2.1 Hz), 8.62 (d, 1 H, J =5.5 Hz), 9.11 51 N-(2-Bromo- Keto 2-Bromo- Magnesium oil (DMSO) 0.79 (t,pyridin-4-yl)-2- butyric pyridin-4- cyclopentyl 3H, J = 7.4 Hz);cyclopentyl-2- acid ylamine bromide 1.42-1.47 (m, 9H); hydroxy-1.75-1.85 (m, 1H); butyramide 2.2-2.3 (m, 1H); 5.35 (s, 1H); 7.82 (dd,1H, J = 1.8 Hz); 8.13 (d, 1H, J = 1.7 Hz); 8.21 (d, 1H, J = 5.6 Hz);10.1 (s, 1H)

Synthesis 52 2-Ethyl-2,6-dihydroxy-hexanoic acid(2-bromo-pyridin-4-yl)-amide (Compound 52) Preparation According toScheme 1, Method 1a Step 52.16-(tert-Butyl-dimethyl-silanyloxy)-2-ethyl-2-hydroxy-hexanoic acid(2-bromo-pyridin-4-yl)-amide

9.3 mL (4.65 mmol, 3 eq) of an 0.5 M solution of4-(tert-butyldimethylsiloxy)butyl magnesium chloride in tetrahydrofuranwere added drop-by-drop to a solution cooled to 0° C. of 400 mg (1.55mmol, 1 eq) of N-(2-bromo-pyridin-4-yl)-2-oxo-butyramide (preparedaccording to Synthesis 1) in 20 mL of tetrahydrofuran. After 30 minutes,the reaction medium was dry concentrated and the residue was dissolvedin 30 mL of ethyl acetate and then washed with an aqueous solutionsaturated in ammonium chloride, and then with water. The organic phasewas then dried over sodium sulphate and then dry concentrated undervacuum. The residue was purified by chromatography on silica and elutedwith a 1/1 (v/v) heptane/ethyl acetate mixture.6-(tert-Butyl-dimethyl-silanyloxy)-2-ethyl-2-hydroxy-hexanoic acid(2-bromo-pyridin-4-yl)-amide was obtained in the form of a colourlessoil.

Step 52.2 2-Ethyl-2,6-dihydroxy-hexanoic acid(2-bromo-pyridin-4-yl)-amide

1 mL (1 mmol, 1.1 eq) of ammonium tetrabutyl fluoride as a 1 M solutionin tetrahydrofuran was added to a solution of 410 mg (0.92 mmol, 1 eq)of 6-(tert-butyl-dimethyl-silanyloxy)-2-ethyl-2-hydroxy-hexanoic acid(2-bromo-pyridin-4-yl)-amide in 20 mL of tetrahydrofuran. The solutionwas agitated at ambient temperature for 16 hours and then dryconcentrated. The residue was dissolved in ethyl acetate and thissolution was washed with an aqueous solution saturated in ammoniumchloride and then with water. The organic phase was dried on sodiumsulphate and then dry concentrated under vacuum. The residue waspurified by chromatography on silica and eluted by a 1/1 (v/v)heptane/ethyl acetate mixture, and then with 100% ethyl acetate.2-ethyl-2,6-dihydroxy-hexanoic acid (2-bromo-pyridin-4-yl)-amide wasobtained in the form of a white solid.

Melting point=103° C. NMR (¹H, DMSO): 0.78-0.82 (t, 3H, J=7.4 Hz),1.03-1.15 (m, 1H), 1.34-1.37 (m, 2H), 1.49-1.58 (m, 3H), 1.73-1.76 (m,2H), 3.32-3.36 (m, 2H), 4.32-4.34 (t, 1H, J=5.1 Hz), 5.48 (s, 1H),7.81-7.83 (dd, 1H, J=5.7, 1.9 Hz), 8.14 (d, 1H, J=1.9 Hz), 8.22 (d, 1H,J=5.7 Hz), 10.10 (s, 1H).

Synthesis 53 2-Hydroxy-2,4-dimethyl-pentanoic acid(2-cyano-6-methoxy-pyridin-4-yl)-amide (Compound 53)

In a 6 mL microwave tube, 0.2 g (0.6 mmol, 1 eq) of2-hydroxy-2,4-dimethyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide (Synthesis 41) was dissolved in 5mL of dimethylformamide and 0.054 g (0.6 mmol, 1 eq) of copper (I)cyanide then added. The reaction mixture was then degassed under vacuum,and then 0.035 g (0.03 mmol, 0.05 eq) of palladium tetrakistriphenylphosphine was added. The tube was sealed and heated for 1 hourat 170° C. in a microwave oven. The reaction mixture was then dilutedwith 50 mL of ethyl acetate, and then filtered on celite; the filtratewas washed three times with 50 mL of water, then dried on magnesiumsulphate, and dry concentrated under vacuum. The residue was purified bychromatography on silica in eluting using a 7/3 (v/v) heptane/ethylacetate mixture. The product obtained was again purified bychromatography on silica by eluting with a 99/1 (v/v)dichloromethane/methanol mixture. 2-Hydroxy-2,4-dimethyl-pentanoic acid(2-cyano-6-methoxy-pyridin-4-yl)-amide is obtained in the form of anoil.

NMR (¹H, DMSO): 0.67 (m, 3H); 0.8 (m, 3H); 1.23 (s, 3H), 1.35-1.45 (m,1H); 1.6-1.7 (m, 2H); 3.76 (s, 3H); 5.68 (s, 1H); 7.54 (d, 1H, J=1.6Hz); 7.92 (d, 1H, J=1.6 Hz); 10.2 (s,H).

Synthesis 54 N-(2-Bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-propionamide(Compound 54)

Under the conditions of preparation ofN-(2-bromo-6-methoxy-pyridin-4-yl)-2-cyclopentyl-2-hydroxy-propionamide(Synthesis 21) described in Method 1a above,N-(2-bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-propionamide was alsoobtained as a secondary product of the reaction in the form of a whitesolid.

NMR (¹H, DMSO): 1.3 (d; 3H; J=8 Hz); 3.8 (s; 3H); 4.1-4.2 (q; 1H; J1=7Hz; J2′=7 Hz); 7.3 (d; 1H; J=1.4 Hz); 7.7 (d; 1H; J=1.4 Hz); 10.2 (s;1H).

Synthesis 55 N-(2-Bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-butyramide(Compound 55)

Under the conditions of preparation ofN-(2-bromo-6-methoxy-pyridin-4-yl)-2-cyclopentyl-2-hydroxy-butyramide(Synthesis 9) described in Method 1a above,N-(2-bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-butyramide was alsoobtained as a secondary product of the reaction in the form of a whitesolid.

NMR (¹H, DMSO): 0.9 (Tr; 3H; J=8 Hz); 1.6 (m; 1H); 1.7 (m; 1H); 3.8 (s;3H); 4.0 (m; 1H); 5.9 (s; 1H); 7.3 (d; 1H; J=1.6 Hz); 7.7 (d; 1H; J=1.6Hz); 10.2 (s; 1H).

Synthesis 56N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-2-ethyl-2-hydroxy-butyramide(Compound 56)

179 mg (0.59 mmol, 1 eq) ofN-(2-bromo-6-methoxy-pyrimidin-4-yl)-oxalamic acid ethyl ester weredissolved in 5 mL of tetrahydrofuran. 0.59 mL (1.77 mmol, 3 eq) of asolution of magnesium ethyl bromide (3 M) in tetrahydrofuran was addeddrop-by-drop at 0° C. After 30 minutes, 5 mL of a solution ofhydrochloric acid (1 M) and 50 mL of ethyl acetate were added. Theorganic phase was washed with 2×50 mL of water, and then dried overmagnesium sulphate and dry concentrated under vacuum. The residue waspurified by chromatography on silica eluting with a 1/1 (v/v)heptane/ethyl mixture.N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-2-ethyl-2-hydroxy-butyramide wasobtained in the form of a white solid.

NMR (¹H, DMSO): 0.8 (t; 6H; J=8 Hz); 1.6 (m; 2H); 1.7-1.8 (m; 2H); 3.9(s; 3H); 5.8 (s; 1H); 8.0 (s; 1H); 9.7 (s; 1H).

Preparation of N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-oxalamic acid ethylester

120 mg (0.59 mmol, 1 eq) of 2-bromo-6-methoxy-pyrimidin-4-ylamine wasdissolved in 10 mL of dichloromethane at 0° C. 0.9 mL (0.65 mmol, 1.1eq) of triethylamine and 80.3 mg (0.59 mmol, 1 eq) of ethyl oxalatechloride were added. After 30 minutes, at ambient temperature, 30 mL ofdichloromethane was added. The organic phase was then washed with 50 mLof a saturated aqueous sodium bicarbonate solution, and then with 2×50mL of water. The organic phase was then isolated and dried overmagnesium sulphate, and then dry concentrated under vacuum.N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-oxalamic acid ethyl ester wasobtained in the form of a pale yellow oil.

Preparation of 2-Bromo-6-methoxy-pyrimidin-4-ylamine

85 mL (34 mmol, 2.2 eq) of an ammonia solution (0.4 M) intetrahydrofuran was added to 5 mg (0.32 mmol, 1 eq) of2,4,6-tribromo-pyrimidine in a 250 mL flask. After 2 hours at ambienttemperature, the reaction mixture was dry concentrated under vacuum. 5.4g of a white solid was obtained. 2.5 g of this solid were then mixedwith 650 mg of sodium hydroxide in 8 mL of methanol. The mixture washeated to 100° C. in a microwave oven for 2 hours. The reaction mixturewas then diluted with 100 mL of ethyl acetate, and then washed with 2×50mL of water. The organic phase was then dried over magnesium sulphateand dry concentrated under vacuum. The residue was purified bychromatography on silica by eluting with a 1/1 (v/v) heptane/ethylacetate mixture. 2-Bromo-6-methoxy-pyrimidin-4-ylamine was obtained inthe form of a white solid.

Synthesis 57 1-Hydroxy-cyclopentanecarboxylic acid(2-bromo-pyridin-4-yl)-amide (Compound 57) Preparation According toScheme 1, Method 1b

2.2 mL (25.9 mmol, 9 eq) of oxalyl chloride were added, drop-by-drop, toa solution, cooled to 0° C., of 1.13 g (8.7 mmol, 3 eq) of1-hydroxy-cyclopentanecarboxylic acid in 20 mL of tetrahydrofuran. Thesolution was agitated at 0° C. for 1 hour, and then at ambienttemperature for 16 hours. The reaction mixture was evaporated dry. Theresidue was absorbed in dichloromethane and added to a solution of 500mg (2.80 mmol, 1 eq) of 5-bromo-pyridin-3-ylamine in 20 ml ofdichloromethane. 1.2 mL (8.6 mmol, 3 eq) of triethylamine was thenadded. The mixture was agitated at ambient temperature for 30 minutes.No initial product remained. The reaction mixture was poured into afrozen mixture of sodium and dichloromethane. The organic phase wasextracted in dichloromethane and then washed in water twice, then driedover sodium sulphate, and dry concentrated under vacuum. The residue wasprecipitated in dichloromethane and heptanes.1-hydroxy-cyclopentanecarboxylic acid (2-bromo-pyridin-4-yl)-amide wasobtained in the form of a white solid.

Melting point=153° C. NMR (¹H, DMSO): 1.70-1.76 (m, 6H), 1.95-2.03 (m,2H), 5.74 (s, 1H), 7.81-7.83 (dd, 1H, J=5.7, 1.9 Hz), 8.14 (d, 1H, J=1.8Hz), 8.23 (d, 1H, J=5.7 Hz), 10.35 (s, 1H).

Synthesis 58 1-Hydroxy-cyclohexanecarboxylic acid(2-bromo-pyridin-4-yl)-amide (Compound 58)

Prepared in the same way as Synthesis 57, by replacing1-hydroxycyclopentane carboxylic acid with 1-hydroxy-cyclohexanecarboxylic acid. 1-Hydroxy-cyclohexane carboxylic acid(2-bromo-pyridin-4-yl)-amide was obtained in the form of a white solid.

Melting point=179° C. NMR (¹H, DMSO) 1.15-1.28 (m, 1H), 1.50-1.71 (m,9H), 5.61 (s, 1H), 7.79-7.81 (dd, 1H, J=5.7, 1.9 Hz), 8.12 (d, 1H, J=1.8Hz), 8.22 (d, 1H, J=5.7 Hz), 10.31 (1H, s).

Synthesis 59 4-(2-Hydroxy-2-methyl-pentanoylamino)-pyridine-2-carboxylicacid methyl ester (Compound 59) Preparation According to Scheme 1,Method 1c

377 mg (2.3 mmol 1.4 eq) of 1,2,4-triazole was added to a solution of220 mg (1.66 mmol, 1 eq) of 2-hydroxy-2-methyl-pentanoic acid in 20 mLof dichloromethane. This solution was agitated for 2 hours at ambienttemperature. The suspension was cooled to 0° C. and the N-sulfinyl4-pyridinamine 2-carboxylic methyl ester was added. The medium wasagitated for 3 hours at 0° C., then at ambient temperature for 16 hours.The precipitate was filtered and the filtrate was washed with water andacidified with hydrochloric acid up to pH 1, and then washed in waterwith water. The aqueous phase was extracted with dichloromethane and theorganic phase was then dried over sodium sulphate and then dryconcentrated under vacuum. The residue was purified by chromatography onsilica gel by eluting with a 1/1 (v/v) mixture of heptanes/ethylacetate. The residue obtained was purified again by chromatography onsilica by eluting with a 2/3 (v/v) heptane/ethyl acetate mixture.4-(2-Hydroxy-2-methyl-pentanoylamino)-pyridine-2-carboxylic acid methylester was obtained in the form of a white solid.

Melting point=122° C. NMR (¹H, DMSO) 0.93-0.97 (t, 3H, J=7.3 Hz),1.25-1.38 (m, 1H), 1.45-1.54 (m, 1H), 1.55 (s, 3H), 1.62-1.69 (m, 1H),1.95-1.98 (m, 1H), 2.35 (s, 1H), 4.02 (s, 3H), 7.98-8.0 (dd, 1H, J=5.5,2.2 Hz), 8.18 (d, 1H, J=2.1 Hz), 8.66 (d, 1H, J=5.5 Hz), 9.06 (s, 1H).

Preparation of N-sulfinyl 4-Pyridinamine 2-carboxylic methyl ester

800 μL (11 mmol, 4.8 eq) of thionyl chloride was added to a solutioncooled to −10° C. of 320 mg (4.7 mmol, 2 eq) of imidazole in 30 mL ofdichloromethane. This solution was agitated for 10 minutes at ambienttemperature. The imidazolium chloride was then filtered. 800 μL (11mmol, 4.8 eq) of thionyl chloride was added to the filtrate at −10° C.and this new solution was agitated for 10 minutes at ambienttemperature. This solution was added at −40° C. to 350 mg (2.3 mmol, 1eq) of 4-amino-pyridine-2-carboxylic acid methyl ester in 20 mL ofdichloromethane. This new solution was agitated at ambient temperaturefor 2 hours. The precipitate was then filtered and the filtrate was dryevaporated. The oily residue is used as is.

Preparation of 2-hydroxy-2-methyl-pentanoic acid Preparation Accordingto Scheme 3

In a 50 mL three-collar flask, 2 g (22.71 mmol, 1 eq) of pyruvic acidwas dissolved in 10 ml of tetrahydrofuran and the solution was cooled to−10° C. 34.1 mL (68.14 mmol, 3 eq) of a propyl magnesium bromidesolution (2 M) in tetrahydrofuran were added drop-by-drop and thereaction mixture was left under agitation for 2 hours at −10° C. 50 mLof an aqueous solution of propyl magnesium bromide (2 M) intetrahydrofuran were added drop-by-drop and the reaction mixture wasleft to agitate for 2 hours at −10° C. 50 mL of an aqueous solution ofhydrochloric acid (1 M) were then added and the organic phase wasextracted with 2×50 mL ethyl acetate, and then dried over magnesiumsulphate and dry concentrated under vacuum. The2-hydroxy-2-methyl-pentanoic acid was then obtained in the form of aslightly pale yellow oil.

Synthesis 60 2-Hydroxy-2-methyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide (Compound 60) PreparationAccording to Scheme 1, Method 1c

In a 50 mL single collar flask 500 mg (2.4 mmol, 1 eq) of 2bromo-6-methoxy-pyridin-4-ylamine were introduced, to which was added 20mL of toluene and 586 mg (4.92 mmol, 2 eq) of thionyl chloride, and themixture heated at reflux for 3 hours. The reaction medium was dryconcentrated under vacuum, and the residue was returned to solution in20 mL of acetonitrile. 325 mg (2.46 mmol, 1 eq) of2-hydroxy-2-methyl-pentanoic acid was then added at ambient temperature.After 16 hours at ambient temperature, the reaction mixture was heatedto 80° C. for 4 hours, then to 60° C. for 3 days, and the reactionmixture was then dry concentrated. The residue was dissolved in 50 mLethyl acetate. The solution was washed twice with 50 mL of an aqueoussolution saturated with ammonium chloride, and then twice with 50 mL ofwater. The organic phase was then dried over magnesium sulphate and thendry concentrated under vacuum. A brown oil was obtained which waspurified by chromatography on silica with a 1/1 (v/v) heptane/ethylacetate mixture as the eluent. A brown solid was then obtained andpurified by chromatography on grafted C18 silica with awater/acetonitrile mixture as the eluent (gradient 5 at 100%acetonitrile). 2-Hydroxy-2-methyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide was obtained in the form of awhite solid.

Melting point=122° C. NMR (¹H, DMSO): 0.9 (t; 3H; J=4 Hz); 1.1-1.3 (m;1H); 1.4 (s; 3H); 1.4-1.5 (m; 1H); 1.6 (m; 1H); 1.7 (m; 1H); 3.9 (s;3H); 5.8 (s; 1H); 7.4 (d; 1H; J=1.4 Hz); 7.8 (d; 1H; J=1.4 Hz); 10.2 (s;1H).

Synthesis 61 2-Hydroxy-2-methyl-pentanoic acid(6-bromo-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (Compound 61)

2 drops of hydrobromic acid at 45% in acetic acid were added to asolution of 100 mg (0.31 mmol, 1 eq) of 2-hydroxy-2-methyl-pentanoicacid (2-bromo-6-methoxy-pyridin-4-yl)-amide (Synthesis 60) in 5 mL ofacetic acid. This solution was heated at reflux for 6 hours. The solventwas evaporated and the residue was absorbed by ethyl acetate and washedwith water. The extracted phase was extracted with ethyl acetate. Theorganic phases were collected and dried over sodium sulphate. Theresidue was purified on silica gel and eluted by a 7/3 (v/v)heptane/ethyl acetate mixture. 2-hydroxy-2-methyl-pentanoic acid(6-bromo-2-oxo-1,2-dihydro-pyridin-4-yl)-amide was obtained in the formof a white solid.

Melting point=188° C. NMR (¹H, DMSO) 0.82-0.85 (t, 3H, J=7.3 Hz),1.12-1.15 (m, 1H), 1.30 (s, 3H), 1.39-1.54 (m, 2H), 1.63-1.66 (m, 1H),5.69 (s, 1H), 7.11 (s, 1H), 7.51 (s, 1H), 9.96 (s, 1H).

Synthesis 62N-(2-Bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-2-methyl-butyramide(Compound 62) Preparation According to Scheme 1, Method 1c

2-Hydroxy-hexanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide wasprepared according to the procedure described in Synthesis 6 byreplacing 2-hydroxy-2-methyl-pentanoic acid by2-hydroxy-2-methyl-butyric acid.N-(2-Bromo-6-methoxy-pyridin-4-yl)-2-hydroxy-2-methyl-butyramide wasobtained in the form of a white solid.

NMR (¹H, DMSO): 0.8 (t; 3H; J=8 Hz); 1.3 (s; 3H); 1.6 (m; 1H); 1.7 (m;1H); 3.81 (s; 3H); 5.7 (s; 1H); 7.3 (d; 1H; J=1.5 Hz); 7.7 (d; 1H; J=1.4Hz); 10.1 (s; 1H).

Synthesis 63 2-Hydroxy-hexanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide (Compound 63) PreparationAccording to Scheme 1, Method 1c

2-Hydroxy-hexanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide wasprepared according to the procedure described in Synthesis 60 byreplacing 2-hydroxy-2-methyl-pentanoic acid by 2-hydroxy-hexanoic acid.2-Hydroxy-hexanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide wasobtained in the form of a colourless oil.

NMR (1H, DMSO): 0.9 (t; 3H; J=8 Hz); 1.3 (m; 4H); 1.5-1.6 (m; 1H);1.6-1.7 (m; 1H); 3.8 (s; 3H); 4.0-4.1 (m; 1H); 5.9 (s; 1H); 7.3 (d; 1H;J=1.4 Hz); 7.7 (d; 1H; J=1.5 Hz); 10.2 (s; 1H).

Synthesis 64 2-Hydroxy-2-isopropyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide (Compound 64) PreparationAccording to Scheme 2, Method 1d Step 64.1N-(2-Bromo-6-methoxy-pyridin-4-yl)-oxalamic acid ethyl ester

In a 250 mL three-collar flask under nitrogen, and at ambienttemperature, 10 g (49.25 mmol, 1 eq) of2-bromo-6-methoxy-pyridine-4-ylamine (initial product 1) were partiallydissolved in 100 mL of dichloromethane. The reaction mixture was cooledto 0° C., and then 7.51 mL (54.18 mmol, 1.1 eq) of triethylamine wereadded, followed by 5.50 mL (49.25 mmol, 1 eq) of ethyl oxalate chloridedrop-by-drop. After 1 hour at ambient temperature, 250 mL of water wasadded followed by 150 mL of dichloromethane. The organic phase was thenextracted and washed twice with 150 mL of an aqueous solution saturatedwith sodium bicarbonate, then with 150 mL of an aqueous solutionsaturated with ammonium chloride, and then twice with water. Afterdrying over magnesium sulphate, the organic phase was concentrated undervacuum and the residue was triturated in diethyl ether.N-(2-Bromo-6-methoxy-pyridin-4-yl)-oxalamic acid ethyl ester wasisolated in the form of a pinkish white solid.

Step 64.2 N-(2-Bromo-6-methoxy-pyridin-4-yl)-oxalamic acid

In a 500 mL three collar flask under nitrogen and at ambienttemperature, 6.70 g (22.10 mmol, 1 eq) ofN-(2-bromo-6-methoxy-pyridin-4-yl)-oxalamic acid ethyl ester (22.10mmol, 1 eq) was dissolved in a mixture of 210 mL of tetrahydrofuran and23 mL of methanol. 4.42 g (110.52 mmol, 5 eq) of sodium hydroxide wasadded at −20° C. under agitation. After 1 hour at −10° C., the reactionmixture was poured into 200 mL of water and approximately 9 mL ofaqueous hydrochloric acid (12 N) was added up to pH 2. The organic phasewas extracted with 250 mL of ethyl acetate, dried over magnesiumsulphate and dry concentrated under vacuum. The white solid residue wastriturated in diethyl ether. N-(2-Bromo-6-methoxy-pyridin-4-yl)-oxalamicacid was isolated in the form of a white solid.

Step 64.3N-(2-Bromo-6-methoxy-pyridin-4-yl)-N′-methoxy-N′-methyl-oxalamide

In a 500 mL three collar flask under nitrogen, and at ambienttemperature, 11.60 g (42.17 mmol, 1 eq) ofN-(2-bromo-6-methoxy-pyridin-4-yl)-oxalamic acid was suspended in 400 mLof tetrahydrofuran, and then 1354 g (42.17 mmol, 1 eq) oftetrafluoroborate of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium was added. After 30 minutes at ambienttemperature, 21.77 mL (126.51 mmol, 3 eq) of N,N-diisopropylethylamineand 4.11 g (42.17 mmol, 1 eq) of chlorohydrate ofN,O-dimethylhydroxylamine were added. After 3 hours and 30 minutes ofagitation at ambient temperature, the reaction mixture was poured into400 mL of aqueous citric acid at 5%. 400 mL of ethyl acetate was addedand the organic phase was extracted and then washed with 300 mL of anaqueous solution saturated with sodium bicarbonate and twice with 300 mLof water, and then dried over magnesium sulphate. After dryconcentration under vacuum,N-(2-bromo-6-methoxy-pyridin-4-yl)-N′-methoxy-N′-methyl-oxalamide acidwas isolated in the form of a white solid.

Step 64.4 N-(2-Bromo-6-methoxy-pyridin-4-yl)-3-methyl-2-oxo-butyramide

In a 100 mL three collar flask under nitrogen, and at ambienttemperature, 2.5 g (7.86 mmol, 1 eq) ofN-(2-bromo-6-methoxy-pyridin-4-yl)-N′-methoxy-N′-methyl-oxalamide wasdissolved in 75 mL of tetrahydrofuran. The reaction mixture was cooledto −15° C., and then 7.86 mL (23.58 mmol, 3 eq) of a solution ofmagnesium dipropyl chloride (initial product 2) (3 M) was then added tothe tetrahydrofuran. After 30 minutes under agitation at 0°, thereaction mixture was treated with 200 mL of an aqueous solutionsaturated with ammonium chloride. The organic phase was extracted with200 mL of ethyl acetate, then washed twice with 100 mL of water, thendried over magnesium sulphate, and dry concentrated under vacuum. Theresidue obtained was chromatographed on silica by eluting with a 9/1(v/v) heptane/ethyl acetate mixture.N-(2-Bromo-6-methoxy-pyridin-4-yl)-3-methyl-2-oxo-butyramide wasisolated in the form of a white solid.

Step 64.5 2-Hydroxy-2-isopropyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide

In a 50 mL three collar flask under nitrogen and at ambient temperature,0.45 g (1.49 mmol, 1 eq) ofN-(2-bromo-6-methoxy-pyridin-4-yl)-3-methyl-2-oxo-butyramide wasdissolved in 13.5 mL of tetrahydrofuran. The reaction mixture was cooledto −20° C., and then 2.24 mL (4.48 mmol, 3 eq) of a magnesium n-propylbromide solution (2 M) was added quickly (initial product 3) was addedquickly to the tetrahydrofuran. After 10 minutes under agitation at−10°, the reaction mixture was poured into 30 mL of an aqueous solutionsaturated with ammonium chloride. The organic phase was extracted with30 mL of ethyl acetate, washed with 30 mL of water, and then dried overmagnesium sulphate. The residue was chromatographed on a silica columnby eluting with a 9/1 (v/v) heptane/ethyl acetate mixture. A product wasrecovered in the form of an oil which was triturated with diisopropylether and heptanes. 2-Hydroxy-2-isopropyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide was isolated in the form of awhite solid.

Melting point=116° C. NMR (¹H, DMSO): 0.78-0.88 (m. 6H); 1.03 (m, 1H);1.4-1.7 (m, 3H); 1.94 (m; 1H); 3.8 (s, 3H); 5.33 (s, 1H); 7.33 (d, J=1.4Hz, 1H); 7.73 (d, J=1.4 Hz, 1H); 9.9 (s, 1H).

Syntheses 65 to 70 Syntheses 65 to 70 are Described in Table 1 Below

The compounds were synthesised according to the above procedure byreplacing the initial products 1, 2 and 3 mentioned in Synthesis 64 bythe initial products mentioned in Table 2. In the context of the ¹H NMRdata shown in Table 2, s=singlet, d=doublet, t=triplet, m=multiplet,q=quartet, J=coupling constant in hertz (Hz).

TABLE 2 Melting Chemical Initial Initial Initial point ¹H NMR Cmpd. #Name Product 1 Product 2 Product 3 (° C.) 400 Mhz 65 2-Hydroxy-2-2-Bromo-6- Magnesium Magnesium 116 (DMSO) isopropyl- methoxy- isopropylsec-propyl 0.78-0.88 (m, 6H); pentanoic acid pyridin-4- bromide bromide1.0-1.1 (m, 1H); (2-bromo-6- ylamine 1.4-1.5 (m, 1H); methoxy- 1.5-1.6(m, 1H), pyridin-4-yl)- 1.6-1.7 (m, 1H); amide 1.9-2.0 (m, 1H); 3.8 (s,3H); 5.33 (s, 1H); 7.33 (d, 1H, J = 1.4 Hz); 7.73 (d, 1H, J = 1.4 Hz);9.9 (s, 1H) 66 2-Butyl-2- 2-Bromo-6- Magnesium Magnesium oil (DMSO) 0.9(t; hydroxy- 6-methoxy- n-butyl n-butyl 6H; J = 8 Hz); hexanoic acidpyridin-4- bromide bromide 1.0-1.1 (m; 2H); (2-bromo-6- ylamine 1.2 (m;4H); methoxy- 1.3-1.4 (m; 2H); pyridin-4-yl)- 1.5-1.6 (m; 2H); amide1.7-1.8 (m; 2H); 3.8 (s; 3H); 5.5 (s; 1H); 7.3 (d; 1H; J = 1.4 Hz); 7.7(d; 1H; J = 1.4 Hz); 10.0 (s; 1H) 67 N-(2-Bromo-6- 2-Bromo-6- MagnesiumMagnesium 162 (DMSO) methoxy- methoxy- cyclopentyl cyclopentyl 1.31-1.58(m, 14H); pyridin-4-yl)- pyridin-4- bromide bromide 1.66-1.67 (m, 2H);2,2- ylamine 2.24-2.28 (m, 2H); dicyclopentyl-2- 3.8 (s, 3H); hydroxy-5.32 (s, 1H); 7.31 (d, acetamide 1H, J = 1.4 Hz); 7.72 (d, 1H, J = 1.4Hz); 9.9 (s, 1H) 68 N-(2-Bromo-6- 2-Bromo-6- Magnesium Magnesium 123(DMSO) 0.86 (m, methoxy- methoxy- isopropyl isopropyl 12H); 2.08 (m,pyridin-4-yl)-2- pyridin-4- bromide bromide 2H); 3.8 (s, 1H); hydroxy-2-ylamine 5.21 (s, 1H); isopropyl-3- 7.33 (d, 1H, J = 1.4 Hz); methyl-7.74 (d, 1H, butyramide J = 1.4 Hz); 9.9 (s, 1H) 69 N-(2-Bromo-6-2-Bromo-6- Magnesium Magnesium 140 (DMSO) methoxy- methoxy-tetrahydropyran- methyl 1.22-1.1.35 (m, 5H); pyridin-4-yl)-2- pyridin-4-4-yl bromide 1.46-1.58 (m, 2H); hydroxy-2- ylamine chloride 1.8-1.9 (m,1H); (tetrahydro- 3.16-3.28 (m, 2H); pyran-4-yl)- 3.8-3.84 (m, 3H);propionamide 3.87-3.91 (m, 2H); 5.75 (s, 1H); 7.33 (d, 1H, J = 1.3 Hz);7.74 (d, 1H, J = 1.4 Hz); 10.1 (s, 1H) 70 2-Hydroxy-2- 2-Bromo-6-Magnesium Magnesium oil (DMSO) 0.8 (m; propyl-hexanoic o-methoxy- butylpropyl 6H); 1.0-1.1 (m; acid (2-bromo pyridin-4- bromide bromide 2H);1.2-1.3 (m; 6-methoxy- ylamine 2H); 1.4-1.6 (m; pyridin-4-yl)- 4H);1.6-1.8 (m; amide 2H); 3.8 (s; 3H); 5.5 (s; 1H); 7.3 (d; 1H; J = 1.4Hz); 7.7 (d; 1H; J = 1.4 Hz); 10.0 (s; 1H)

Synthesis 71 (R)-2-Hydroxy-2,4-dimethyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide Compound 71A(S)-2-Hydroxy-2,4-dimethyl-pentanoic acid(2-bromo-6-methoxy-pyridin-4-yl)-amide (Compound 71B)

The two enantiomers of the racemic mixture prepared in Synthesis 41 wereseparated by HPLC (high pressure liquid chromatography) on a chiralstationary phase Chiralpak type Ia, Chiral Technologies, diameter 2 cm,length 25 cm, eluting with 93/7 (v/v) heptane/isopropanol containing0.1% (v/v) trifluoroacetic acid. The flow rate was 18 mL/minute. Theinjection volume was 1 mL of a solution of 20 mg of the racemic mixturedissolved in a 1/1 (v/v) mixture of heptane/isopropanol. The retentiontimes of the two enantiomers were 8.38 minutes and 9.70 minutes. After 6injections, 40 mg of the two enantiomers were obtained as oils aftersolvent evaporation.

Analysis 71

Further analysis was performed using chiral HPLC (Chiralpak type Ia,Chiral Technologies, 250×4, 6 mm, eluent 93/7 (v/v) heptane/isopropanolcontaining 0.1% (v/v) trifluoroacetic acid with a flow rate of 1mL/minute for 20 minutes. Compound 71A had a retention time of 6.77minutes, and Compound 71B had a retention time of 8.71 minutes.

The absolute configuration of Compound 71B was determined using X-raydiffraction (XRD), and found to be the (S) configuration. Accordingly,Compound 71A was determined to be in the (R) configuration.

Syntheses 72-80

Separation of the enantiomers in a number of racemic mixtures (obtainedin earlier syntheses) was performed in the same manner as described inSynthesis 71. Analysis was done in the same manner as described inAnalysis 71, with the following modifications:

Racemic Mixture Analysis (Compound Compound retention No.) Name Analysiselution No. Time (min) 8 2-Hydroxy-2- (as in Analysis 71) 72A 6.94methyl-hexanoic 72B 8.45 acid (2-bromo-6- methoxy-pyridin- 4-yl)-amide 9N-(2-Bromo-6- 92/8 (v/v) heptane/ 73A 6.94 methoxy-pyridin- isopropanol73B 17.74 4-yl)-2- containing 0.1% cyclopentyl-2- trifluoroacetic acidhydroxy- over 30 minutes butyramide 13 N-(2-Bromo-6- 85/15 (v/v)heptane/ 74A 4.66 methoxy-pyridin- isopropanol 74B 5.13 4-yl)-2-ethyl-2-containing 0.1% hydroxy-3-methyl- trifluoroacetic acid butyramide over15 minutes 19 2-Ethyl-2- (as in Analysis 71) 75A 7.23 hydroxy- 75B 9.74pentanoic acid (2- bromo-6- methoxy-pyridin- 4-yl)-amide 25N-(2-Bromo-6- (as in Analysis 71) 76A 9.83 methoxy-pyridin- 76B 12.884-yl)-2-hydroxy- 2,3-dimethyl- butyramide 51 N-(2-Bromo- 93/7 (v/v)heptane/ 77A 10.26 pyridin-4-yl)-2- isopropanol 77B 28.59 cyclopentyl-2-containing 0.1% hydroxy- trifluoroacetic acid butyramide over 35 minutes60 2-Hydroxy-2- (as in Analysis 71) 78A 7.61 methyl-pentanoic 78B 8.73acid (2-bromo-6- methoxy-pyridin- 4-yl)-amide 64 2-Hydroxy-2- 90/10(v/v) heptane/ 79A 6.05 isopropyl- isopropanol 79B 10.86 pentanoic acid(2- containing 0.1% (v/v) bromo-6- trifluoroacetic acid methoxy-pyridin-over 30 minutes 4-yl)-amide 1 2-Hydroxy-2- 97/3 (v/v) heptane/ 80A 32.98methyl-hexanoic isopropanol 80B 36.50 acid (2-bromo- containing 0.02%pyridin-4-yl)- (v/v) trifluoroacetic amide acid over 50 minutes

Biological Studies Study 1

The N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides described hereinexhibit androgen receptor (AR) inhibiting properties. This AR inhibitingactivity was measured in a transactivation test by the dissociationconstants KdR (rest), KdA (active), and Kdapp (apparent).

A compound may be said to be an AR inhibitor if it has a dissociationconstant, Kdapp, of less than or equal to 1 μM, and a KdR/KdA ratio ofless than or equal to 10 in a transactivation test.

Preferred AR type receptor inhibitors have a dissociation constant ofless than or equal to 500 nM, and more preferably less than or equal to100 nM.

The transactivation test is carried out in the cell line PALM (PC3androgen receptor Luciferase MMTV), which is a stable transfectantcontaining the plasmids PMMTV-neo-Luc (reporter gene) and pSG5puro-AR.

In this study, the affinity of each test compound for the 2 states ofthe receptor (KdR and KdA) is determined together with the apparent Kd(KdApp). This constant depends upon the 2 Kd's (KdR and KdA), but alsodepends on the initial equilibrium of the receptor between the activestate and rest state (L₀) and on its expression rate. It is determinedby the following formula:

1/KdApp=(L ₀/(1+L ₀))×(1/KdR)+(1/(1+L ₀))×(1/KdA)

In order to determine these constants, “cross curves” of the testcompound against a reference agonist, methyl trienolone, are carried outon a 96-well plate. The test compound is used in 10 concentrations andthe reference agonist in 7 concentrations.

A Kdapp values for a number of compounds are reported in Table 3.

TABLE 3 Compound No. Kdapp (nM) 1 75 8 30 23 15 24 300 32 100 41 20 43100 59 6000

The following compounds were found to have a Kdapp of 10 μM or less:

Compounds 1, 8, 9, 13, 19, 23, 24, 25, 27, 32, 38, 41, 43, 51, 59, 60,64, 66, 68, 69, 71A, 71B, 72A, 72B, 73A, 73B, 74A, 74B, 75A, 75B, 76A,76B, 77A, 77B, 78A, 78B, 79A, 79B, 80A, and 80B.

The following compounds were found to have a Kdapp of 1 μM or less:

Compounds 1, 8, 9, 13, 19, 23, 24, 25, 27, 32, 38, 41, 43, 51, 60, 64,66, 68, 69, 71A, 71B, 72A, 72B, 73A, 73B, 74A, 74B, 75A, 75B, 76A, 76B,77A, 77B, 78A, 78B, 79A, 79B, 80A, and 80B.

The following compounds were found to have a Kdapp of 300 nM or less:

Compounds 1, 8, 9, 13, 19, 23, 24, 25, 27, 32, 38, 41, 43, 51, 60, 64,66, 68, 71A, 71B, 72A, 72B, 73A, 73B, 74A, 74B, 75A, 75B, 76A, 76B, 77A,77B, 78A, 78B, 79A, 79B, 80A, and 80B.

The following compounds were found to have a Kdapp of 100 nM or less:

Compounds 1, 8, 9, 13, 19, 23, 25, 32, 41, 43, 51, 60, 64, 66, 68, 71A,71B, 72A, 72B, 73A, 73B, 74A, 74B, 75A, 75B, 76A, 76B, 77A, 77B, 78A,78B, 79A, 79B, and 80A.

The following compounds were found to have a Kdapp of 30 nM or less:

Compounds 8, 9, 13, 19, 23, 25, 41, 51, 64, 68, 71A, 71B, 72A, 73A, 74A,74B, 76A, 77A, 77B, 79B, and 79A. Study 2 In Vivo Study Animal Modelwith Reduction in the Size of the Sebaceous Glands

The model of the sebaceous gland of the ear of a Syrian hamsterdescribed by Plewig and Luderschmidt in J. Inv. Derm., (1977), pp.171-176 is a classical tool for the in vivo study of the function of thesebaceous gland. In fact, the inner faces of the ear lobes of thehamster contain a high number of sebaceous glands described as beingsimilar to those of human sebaceous follicles in terms of certaincharacteristics, including their morphology and response to androgensand anti-androgens. In fact the growth and lipogenesis of the sebaceousglands on the inner face of the ear of Syrian hamsters depend on theandrogens. The anti-androgenic activity of test compounds can be easilyevaluated by measuring the size of the sebaceous glands. Moreover, thismodel has been selected to evaluate the efficacy of the antagonists ofthe receptor to the androgens on the sebaceous gland.

Test compounds were evaluated according to the following protocol: malehamsters aged weeks were treated daily for 24 days on the inner face ofthe right ear with 30 μL of a solution of the test compound to beevaluated in absolute ethanol. For each test compound, groups weretreated with solutions at a range of concentrations (e.g., from 0.01 g%/mL to 3 g %/mL), as well as absolute ethanol used as a control. (Aconcentration of 3 g %/mL means a concentration of 0.03 g/mL.)

At the end of the study, samples were taken from the treated ears. Theskin of the inner face of the ear was separated from the cartilage.Under a binocular magnifying glass, two zones of 4 mm² were numbered.The size of the sebaceous glands was measured on the numerical images bymanually trimming the glands by means of image analysis software(TINA.20). For each image some twenty glands were measured. The averagearea of the sebaceous glands was calculated for each treatment group.

A Student t-test for independent groups comparing each dose with vehiclewas carried out to compare the average size of the sebaceous glands as afunction of the doses applied. When the evolution of the effect isrepresented graphically as a function of the administered dose of testcompound, the curve obtained is sigmoid in shape. In the median part,this sigmoid may be likened to a straight line. The dose correspondingto 50% of the maximum effect corresponds graphically to the pointlocated in the centre of the linear section defined as “effective dose50”. This DE₅₀ characterises the potency of the test compound.

Results obtained in this test for certain compounds described herein areshown in Table 4. For example, for Compound 1, 50% of the maximum effectwas observed at a concentration of 0.2 g %/mL.

The percent reduction in the size of the sebaceous glands observedfollowing treatment with a 1 g %/mL solution of test compound, ascompared to the control, are also shown in Table 4. For example, forCompound 1, a concentration of 1 g %/mL caused a 53% reduction in thesize of the sebaceous glands as compared to control.

TABLE 4 Reduction of sebaceous DE₅₀ glands (following Compound No. (g%/mL) treatment at 1 g %/mL)  1 0.20 53%  8 0.10 56% 19 0.07 61% 23 0.0451% 41 0.04 61% 43 0.20 44% 68 0.04 57% 71B 0.04 56% 72A 0.06 48% 72B0.26 46% 74B 0.01 61% 76A 0.02 58% 78B 0.04 50% 79A 0.04 48% 80A 0.2051%

The foregoing has described the principles, preferred embodiments, andmodes of operation of the present invention. However, the inventionshould not be construed as limited to the particular embodimentsdiscussed. Instead, the above-described embodiments should be regardedas illustrative rather than restrictive, and it should be appreciatedthat variations may be made in those embodiments by workers skilled inthe art without departing from the scope of the present invention.

1. A compound of formula (1), or a pharmaceutically acceptable salt,hydrate, or solvate thereof:

wherein: R¹ is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy,—S(O)_(m)—C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆alkyl-OH, —(CH₂)_(i)—C₁₋₆ alkyloxy, —(CH₂)_(j)—O—C₁₋₆ fluoroalkyl,COR^(a), CN, NO₂, NR⁵R⁶, or a halogen atom; R² is a hydrogen atom, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(n)—C₁₋₆ alkyl, C₁₋₆fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆ alkyl-OH, —(CH₂)_(k)—C₁₋₆alkyloxy, —(CH₂)_(l)—O—C₁₋₆ fluoroalkyl, COR^(b), CN, NO₂,NR^(5′)R^(6′), OH, or a halogen atom; R³ and R⁴ are identical ordifferent and are a hydrogen atom, C₁₋₁₂ alkyl, C₃₋₉ cycloalkyl, C₁₋₆fluoroalkyl, —C₁₋₆ alkyl-OH, —(CH₂)_(p)—C₁₋₆ alkyloxy, —(CH₂)_(q)—C₃₋₉cycloalkyl, —(CH₂)_(r)—C₁₋₆ fluoroalkyl, —(CH₂)_(s)—O—C₁₋₆ fluoroalkyl,phenyl, heteroaryl, heterocyclyl group, —(CH₂)_(t)-phenyl, or—(CH₂)_(v)-heteroaryl, wherein each phenyl and heteroaryl is optionallysubstituted with one to three identical or different R^(c) groups; andadditionally, R³ and R⁴, together with the carbon atom carrying them,may form a C₃₋₉ cycloalkyl group or a heterocyclyl group, such astetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydro-1-oxo-thiopyranyl, or tetrahydro-1,1-dioxo-thiopyranyl; R^(c)is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyloxy, —S(O)_(u)—C₁₋₆ alkyl,C₁₋₆ fluoroalkyl, C₁₋₆ fluoroalkyloxy, C₁₋₆ alkyl-OH, COR^(d), CN, NO₂,NR⁹R¹⁰, OH, or a halogen atom; R^(a), R^(b), and R^(d) are identical ordifferent and are C₁₋₆ alkyl, C₁₋₆ alkyloxy, or NR⁷R⁸; R⁵, R^(5′), R⁶,R^(6′), R⁷, R⁸, R⁹ and R¹⁰ are identical or different and are a hydrogenatom, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, or —(CH₂)_(w)—C₃₋₇ cycloalkyl; andadditionally, R₅ and R₆, together with the nitrogen atom carrying them,may form a heterocyclyl group; and additionally, R_(5′) and R_(6′),together with the nitrogen atom carrying them, may form a heterocyclylgroup; and additionally, R₇ and R₈, together with the nitrogen atomcarrying them, may form a heterocyclyl group; and additionally, R₉ andR₁₀, together with the nitrogen atom carrying them, may form aheterocyclyl group; i, j, k, l, p, q, r, s, t, v, and w are different oridentical and are 1, 2 or 3; and m, n, and u are different or identicaland are 0, 1 or 2.